Crosstalk Between Integrin and Receptor Tyrosine Kinase Signaling in Breast Carcinoma Progression

BMB reports

Mini Review

Crosstalk between integrin and receptor tyrosine kinase signaling in breast carcinoma progression

Young Hwa Soung, John L. Clifford & Jun Chung* Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130

This review explored the mechanism of breast carcinoma pro- cancer originates from breast epithelial cells that are trans- gression by focusing on integrins and receptor tyrosine kinases formed into metastatic carcinomas. Metastatic potential and re- (or growth factor receptors). While the primary role of integrins sponsiveness to treatment vary depending on the expression of was previously thought to be solely as mediators of adhesive hormone receptors such as estrogen receptor and progesterone interactions between cells and extracellular matrices, it is now receptor (5), RTKs such as ErbB-2, epidermal growth factor re- believed that integrins also regulate signaling pathways that ceptor (EGFR), and hepatocyte growth factor receptor, c-Met control cancer cell growth, survival, and invasion. A large (6), and integrins (7). Major integrins expressed on breast epi- body of evidence suggests that the cooperation between in- thelial cells include α2β1, α3β1, αvβ3, αvβ5, αvβ6, α5β1, tegrin and receptor tyrosine kinase signaling regulates certain α6β1, and α6β4 (7). Among these, this review focuses on signaling functions that are important for cancer progression. αvβ3, α5β1, and α6β4, all of which are upregulated in in- Recent developments on the crosstalk between integrins and vasive breast carcinoma and have well established relation- receptor tyrosine kinases, and its implication in mammary tu- ships with RTKs (8). These integrins serve as receptors for vi- mor progression, are discussed. [BMB reports 2010; 43(5): tronectin, fibronectin, and laminin, respectively (9), and con- 311-318] tribute to the survival and invasion of mammary tumors. Model systems describing the mechanisms and relevance of these integrin-RTK interactions will be discussed. INTRODUCTION Integrin interaction with ECM Cancer progression is a multi-step process that enables tumor cells to invade through extracellular tissues and metastasize to Integrins represent a major family of receptors that mediate distal organs (1). Compelling recent evidence demonstrates cell adhesion to the ECM. To date, at least 18 α and 8 β in- that cooperation between signals from the extracellular matrix tegrin subunits have been discovered (10). These non-homolo- (ECM) and growth factors enhances malignant behaviors of ag- gous, transmembrane α and β subunits dimerize to form 24 gressive cancer cells, such as proliferation, migration, survival, different integrins, each with distinct and sometimes over- and invasion (2). Intracellular signals generated by growth fac- lapping specificities for various ECM proteins. While the pri- tors and their receptor tyrosine kinases (RTKs) are generated in- mary role of integrins was thought to be as mediators of adhe- dependently from those produced by interaction between the sive function, integrins also regulate cellular biological proc- ECM and integrin, and the synergy between these signals plays esses related to cell morphology, proliferation, survival, migra- an important role in tumor growth and metastasis (3). There- tion, and invasion (11). In other words, integrins relay cues fore, defining the mechanism by which these two signaling from the ECM to intracellular signaling machinery upon ligand pathways cooperate is essential for understanding cancer pro- binding, a process called "Outside-in Signaling" (9). On the gression. other hand, intracellular signaling activated by other receptors This review focuses on the evidence for crosstalk between could induce conformational changes in integrins, thus alter- integrin and RTKs in breast carcinoma progression. Breast can- ing their functional activity, a process called "Inside-out Signa- cer is the most common form of cancer among women and is ling" (12). Therefore, integrins and RTKs can exchange or am- the second leading cause of cancer-related death (4). Breast plify their signaling pathways via both "Outside-in" and "Inside-out" signaling. *Corresponding author. Tel: 318-675-8797; Fax: 318-675-5180; Downstream signaling events induced by integrin-ECM in- E-mail: [email protected] teractions include Ras, Phosphop-inositol-3-kinase (PI3 Kinase), MAP kinase, focal adhesion kinase (FAK), Src, Akt, integrin- Received 1 May 2010 linked kinase (ILK), Abl and Rac, Rho, and cdc42 small Keywords: Breast carcinoma progression, Crosstalk, Growth factor GTPases (13-16). In addition, integrin-ECM interactions induce receptors, Integrin, Invasion, Survival the phosphorylation of key tyrosine residues of integrin sub- http://bmbreports.org BMB reports 311 Crosstalk between integrins and RTKs Young Hwa Soung, et al.

units such as β3 and β4, which results in recruitment of signal- tors. For example, αvβ3 integrin associates with insulin-like ing adaptor molecules such as Shc, Shp-2, and Crk (17-19). growth factor receptor (IGFR-1), platelet-derived growth factor These adaptor molecules not only transmit integrin-dependent receptor (PDGFR) (24, 25), and vascular endothelial growth signals, but also contribute to crosstalk with other signaling re- factor receptor-2 (VEGFR2) (26). Additionally, α6β4 integrin ceptors including RTKs (20-22). It is interesting to note that in- has been shown to associate with ErbB2 (27), c-Met (28), EGFR tracellular signaling events activated by integrin ligation are al- (20), and Ron (29). These associations suggest that signaling so influenced by growth factor stimulation. Indeed, integrin- cooperation between integrins and RTKs may be the result of ECM interactions significantly amplify growth factor-mediated receptor co-clustering upon cell adhesion or growth factor signaling events (23), which suggests that synergy between in- stimulation. Growth factor stimulation of RTKs or ECM-integrin tegrin and RTK signaling could maximize biochemical res- interactions induces an increase in the local concentration of ponses. integrins and RTKs at focal adhesions and at leading edges of carcinoma cells, such that crosstalk could occur even without Evidence for integrin and RTK crosstalk direction physical association by alteration of the intracellular localization of integrins (30). Considering that neither α nor β integrin subunits possess cata- The mode of signaling cooperation between integrins and lytic activity, it is possible that multiple mechanisms may regu- RTKs could be reciprocal as well as uni-directional. Bi-direc- late crosstalk between integrins and RTKs. The most compel- tional cooperation between the two signaling systems was ling evidence comes from direct, physical association between demonstrated for the αvβ3-IGF receptor (31) and αvβ3-PDGF-α integrins and RTKs. Co-immunoprecipitation assays have been complex (32), whereupon signaling pathways activated by used to identify biochemical interactions between these recep- both integrin engagement and growth factors converge down-

Fig. 1. Signaling pathways mediated by α6β4 integrin-RTKs crosstalk. α6β4 integrin in Hemidesmosomes (HDs) has no signaling function but does provide structural support to the epithelia. The tumor microenvironment induces PKC-α-dependent phosphorylation of key Ser residues in the β4 integrin cytoplasmic tail, resulting in HD disassembly. Mobilization of α6β4 from HDs allows association of α6β4 with actin filament-rich sub domains of membrane structures in which functional interactions with RTKs occur, such as lipid rafts. Several examples in which α6β4 associates with RTKs are shown. (A) α6β4 is physically and functionally associated with ErbB2 and EGFR. The association of EGFR with α6β4 is mediated by SFKs (Fyn) activation. (B) MSP induces association of α6β4 with Ron through 14-3-3, which acts as a linker molecule. (C) Cooperative signaling between α6β4 and c-Met is responsible for various aspects of breast cancer progression, although the constitutive and physical interaction between c-Met and α6β4 remains controversial. PI-3K/Ras are major downstream signaling pathways mediated by α6β4-RTK crosstalk.

312 BMB reports http://bmbreports.org Crosstalk between integrins and RTKs Young Hwa Soung, et al.

stream at common signaling effectors. Uni-directional, in- an orphan receptor of the EGFR family, in several breast carci- tegrin-dependent RTK activation was demonstrated for β1 in- noma cells (27, 46). This association is required for the PI3K/ tegrin-dependent EGFR activation (21). β1 integrin ligation by AKT pathway to stimulate α6β4-dependent breast carcinoma adhesion leads to the c-Src dependent recruitment of EGFR cell motility and invasion (47). α6β4 also enhances ErbB3 ex- and p130Cas, and subsequently to phosphorylation and activa- pression in breast cancer cells, and cooperation between these tion of EGFR in an EGF-independent manner (21). Finally, two receptors is required for PI3K activation (48). EGFR con- α6β4 integrin is an example of uni-directional, growth fac- tributes to α6β4-dependent invasion via disruption of hemi- tor-dependent integrin activation. Growth factor-dependent ac- desmosomes (HD) as well as subsequent activation of Fyn, a tivation of EGFR and c-Met increases the phosphorylation of Src family kinase (20, 33). A more recent report demonstrated key serine and tyrosine residues of the β4 integrin cytoplasmic that crosslinking of α6β4 results in the clustering of EGFR on tail (20, 33-35). Phosphorylated α6β4 amplifies EGFR and the plasma membrane of breast carcinoma cells, which pro- c-Met signaling in a ligand-independent manner, since an ex- motes Rho activation for the enhancement of cell motility and tracellular domain deletion mutant of β4 integrin could still invasion (49). mediate crosstalk (36). Another example of the α6β4-RTK interaction was demonstrated by its relationship with the Hepatocyte growth factor α6β4 integrin and RTK association (HGF) receptor, c-Met. Trusolino et al demonstrated that α6β4 physically associates with c-Met, functioning as an adaptor α6β4 integrin is a receptor of the laminin family of extra- molecule for the amplification of c-Met signaling in invasive cellular matrix proteins, although increasing evidence suggests breast carcinoma cells (28). Additional studies showed that that it can signal independently of laminin binding (30, 37, HGF stimulation mediates tyrosine phosphorylation of the β4 38). Due to its ubiquitous expression in most epithelial cells, integrin subunit and enhances anchorage-independent growth α6β4 was originally thought to maintain the integrity of epi- of breast cancer cells through Gab1 and Src (17). While the thelia based on its ability to mediate the formation of hemi- constitutive and physical interaction between α6β4 and c-Met desmosomes (HDs), which are responsible for linking inter- remains controversial (50), it appears that their functional inter- mediate filaments with laminins in the basement membrane actions play a key role in breast carcinoma progression. The (38, 39). However, recent evidence has established that this first study to explain the mechanism of α6β4-RTK complex for- integrin is associated with reduced survival and poor prognosis mation was conducted by Santoro et al. (29). Macrophage in a number of human cancers (39-41). Our studies and others stimulating protein (MSP) receptor, Ron (a c-Met related kin- also confirmed that α6β4 has functions associated with carci- ase), stimulates PKC-dependent auto-phosphorylation as well noma progression (28, 42, 43). The remaining question, there- as phosphorylation of β4 integrin upon MSP activation in kera- fore, is how α6β4 integrin could exert two different functions tinocytes. Phosphorylated Ron and α6β4 are able to recruit in normal epithelia vs. aggressive carcinoma cells. The current 14-3-3, which acts as a linker molecule in the formation of a model states that α6β4 in epithelial cells simply contributes to Ron-α6β4 complex (29). These data suggest that formation of tissue integrity and structural support via association with the integrin-RTK complex can be triggered by oncogenic sti- HDs, whereas in carcinoma cells the tumor microenvironment muli. Altogether, it is apparent that the α6β4-RTK interaction leads to EGFR/PKC-α- dependent phosphorylation of the β4 in- contributes to various aspects of carcinoma behavior, although tegrin cytoplasmic tail at specific Ser residues, which then in- the precise nature of their interaction remains to be deter- duces disassembly of HDs (Fig. 1) (33, 34). Subsequent mobi- mined. lization of α6β4 from HDs is essential for signaling and is characteristic of invasive carcinoma cells (30). Once released αvβ3 integrin and RTK association from HDs, Cys residues of the membrane proximal region of β4 integrin are palmitoylated, which allows α6β4 to be in- The αvβ3 integrin is a vitronectin binding receptor whose ex- corporated into lipid rafts (33, 34). Lipid rafts are sphingolipid, pression is upregulated in metastatic breast carcinoma cells cholesterol-rich microdomains of the plasma membrane that (51, 52). Due to its high expression in both breast tumor and contain many signaling receptors all of which are in close angiogenic epithelial cells, αvβ3 is an attractive therapeutic tar- proximity (44, 45). Once α6β4 localizes to lipid rafts, its sig- get. The αvβ3 blocking antibodies LM609 and etaracizumab, a naling function is supposedly enhanced through crosstalk with humanized version of LM609, are currently being tested in signaling receptors such as RTKs, since lipid rafts are rich in clinical trials and have been shown to effectively block both RTKs. The signaling competent form of α6β4 has the potential angiogenic activity (53) and bone metastsis (54). to form complexes with specific RTKs that mediate key signal- Multiple RTKs has been shown to associate with αvβ3 (55), ing pathways essential to breast carcinoma behavior (Fig. 1). and the blocking ligand occupancy of αvβ3 reduces RTK sig- The first evidence for the association of α6β4 with RTKs naling (Fig. 2). For example, αvβ3-mediated adhesion enhan- came from studies involving EGFR family members. Falcioni et ces IGFR-1 signaling, since inhibition of αvβ3 ligand occu- al demonstrated that α6β4 integrin may associate with ErbB2, pancy by the disintegrin echistatin reduces phosphorylation of http://bmbreports.org BMB reports 313 Crosstalk between integrins and RTKs Young Hwa Soung, et al.

Fig. 2. Signaling pathways mediated by αvβ3 integrin-RTKs crosstalk. (A) IGFR-1 requires vitronectin binding of αvβ3 for maximal IGF-1 response, such as MAPK activation and carcinoma cell motility. Blockage of ligand binding to αvβ3 recruits the tyrosine phosphatase Shp2 and reduces IGFR1 phosphorylation. (B) Crosstalk between αvβ3 and c-Met is involved in OPN-induced carcinoma migration, leading to bone metastasis of breast carcinoma. (C) VEGF stimulates c-Src-dependent phosporylation of the β3 cytoplasmic domain, leading to complex formation between αvβ3 and VEGFR. αvβ3 and c-Met complex are involved in PI-3K activation and the angiogenic response. (D) PDGF stimulation induces Shc-dependent αvβ3-PDGF complex formation that contributes to carcinoma proliferation.

IGFR-1 by recruiting the tyrosine phosphatase Shp2 (Malie 2002). ways that induce αvβ3-RTK interaction are attractive strategies αvβ3 also cooperates with c-Met to enhance OPN (osteopontin)- for developing novel anti-cancer therapeutics. induced mammary epithelial cell migration (56, 57). This evidence suggests a potential role for the αvβ3-RTK complex in α5β1 integrin and RTK association bone metastasis of breast cancer. Association between PDGFR and αvβ3 was demonstrated in oligodendrocytes (32, 58), and α5β1 Integrin is the major receptor for fibronectin (62) and PDGF-dependent mitogenic activity requires association be- contributes to breast cancer survival and metastasis. Both ele- tween αvβ3 and PDGFR. PKC mediates PDGF-induced activa- vated levels and activity of α5β1 have been implicated in tion of αvβ3, which leads to an increase in matrix binding of drug-resistant breast carcinoma cells (63). The mechanism by αvβ3 and αvβ3-dependent oligodendrocyte proliferation. which α5β1 promotes invasion of breast carcinoma cells in- In addition to its role in vitronectin-dependent migration volves the recruitment or activation of matrix metalloproteinase and proliferation, αvβ3 contributes to angiogenesis through 2 (MMP-2) collagenase on the cell surface (64). The α5β1- physical and functional interactions with vascular endothelial fibronectin interaction also causes constitutive invasiveness of growth factor receptor-2 (VEGFR2) (26, 59). Treatment with a prostate cancer cells via MMP-1 activation, indicating its major ligand blocking antibody against αvβ3 integrin inhibits VEGF- role in matrix metalloproteinase regulation (65). Further, α5β1- stimulated VEGFR-2 phosphorylation (26). VEGF stimulation RTK interactions were reported to contribute to the invasive leads to c-Src dependent phosphorylation of the β3 cytoplas- phenotype of cancer cells (Fig. 3). While the major ligand of mic domain (Y747, Y759), which contributes to physical asso- α5β1 is fibronectin, fibrinogen and urokinase type plasmi- ciation of αvβ3 with VEGFR2 (22, 60). Finally, a novel para- nogen activator receptor (uPAR) can also interact with α5β1 as digm for integrin-RTK crosstalk was recently reported that ligands. For example, activated EGFR and uPAR form a ternary showed Fibroblast growth factor-1 (FGF1) directly binds to complex with α5β1 that promotes cancer cell migration, in- αvβ3, which regulates FGF1-dependent angiogenesis via ex- vasion, proliferation, and survival by activation of the ERK tracellular signal-regulated kinase (Erk) and Akt (61). All these pathway (66). The results suggest that, in aggressive carcinoma data suggest that the αvβ3-RTK complex has multiple roles in cells, α5β1 can interact with EGFR through overexpression of carcinoma progression, including migration, invasion, bone uPAR. metastasis, and angiogenesis (Fig. 2). Therefore, targeting path- In addition to its role in carcinoma cell invasion, α5β1 is

314 BMB reports http://bmbreports.org Crosstalk between integrins and RTKs Young Hwa Soung, et al.

Fig. 3. Signaling mediated by α5β1 integrin-RTKs crosstalk. (A) uPAR and fibronectin form a ternary complex that contains uPAR, EGFR, and α5β1 resulting in activation of the Erk pathway. (B) Ang-1 stimulation induces α5β1-Tie2 association, which recruits the p85 subunit of PI-3K along with FAK to the α5 cytoplasmic domain. This interaction is implicated in PI3K-mediated angiogenesis. (C) α5β1 forms a complex with EGFR via recruitment of p85 to α5β1 through ErbB3 phosphorylation, resulting in PI3K activation. (D) HGF forms hetero-complexes with the matrix ligands (vitronectin and fivronectin) of αvβ3 and α5β1 These hetero-complexes promote interaction of c-Met with αvβ3 and α5β1. implicated in the regulation of endothelial cell function and Summary angiogenesis through the Tie-2 receptor, which binds to An- giopoetin-1 (Ang-1) and Angiopoetin-2 (Ang-2) (67). In endo- Collaborative activity between integrins and RTKs provide a thelial cells, the physical interaction of α5β1 and Tie2 with mechanism for signaling systems important to carcinoma Ang1 results in the phosphorlyation of the p85 subunit of PI3K progression. This review summarized multiple examples in as well as FAK and the efficient transmission of PI3K/AKT sig- which breast carcinoma cells respond to environmental cues nals (67). Consistent with this evidence, a study demonstrated related to growth factors and extracellular matrix molecules by that functional association of α5β1 with VEGFR3 plays a role focusing on integin-RTK interactions. Further study will con- in the proliferation of lymphatic endothelial cells and angio- tinue to generate insights into the molecular mechanisms un- genesis through activation of the PI3k/AKT pathway (68). In derlying the physical and functional partnerships between another example, α5β1 complexes with EGFR and ErbB3 in in- these receptors. Eventually, such data will provide the basis for testinal epithelial cells, which leads to recruitment of p85 to developing novel therapeutic interventions that target the inter- the EGFR-α5β1 complex through ErbB3 phosphorylation fol- action between integrins and RTKs. lowed by enhanced PI3K signaling. However, the nature of this ternary complex remains to be determined (69). Acknowledgements Finally, the HGF receptor c-Met, which associates with US Army Medical Research Program Grant (BC001077) and α6β4 and αvβ3, also interacts with α5β1 (70). It is interesting Wendy Will Case Cancer Foundation Grant supported the to note that the c-Met ligand HGF forms hetero-complexes work discussed in this review from the author’s laboratory. with vitronectin and fibronectin, allowing simultaneous association of c-Met with αvβ3 and α5β1 (70). Indeed, the activity REFERENCES and phosphorylation level of c-Met in the presence of vitronectin and fibronectin were significantly enhanced by for- 1. Hanahan, D. and Weinberg, R. A. (2000) The hallmarks of mation of this heterocomplex (71). Overall, these studies dem- cancer. Cell 100, 57-70. onstrate the importance of the α5β1-RTK complex in regulat- 2. Larsen, M., Artym, V. V., Green, J. A. and Yamada, K. M. ing carcinoma invasion as well as in vascular stabilization that (2006) The matrix reorganized: extracellular matrix re- is essential for angiogenesis (Fig. 3). modeling and integrin signaling. Curr. Opin. Cell Biol. 18,

http://bmbreports.org BMB reports 315 Crosstalk between integrins and RTKs Young Hwa Soung, et al.

463-471. naling by the adaptor protein Shc. J. Cell Biol. 147, 1561- 3. Giancotti, F. G. and Ruoslahti, E. (1999) Integrin sig- 1568. naling. Science 285, 1028-1032. 20. Mariotti, A., Kedeshian, P. A., Dans, M., Curatola, A. M., 4. Perou, C. M., Sorlie, T., Eisen, M. B., van de Rijn, M., Gagnoux-Palacios, L. and Giancotti, F. G. (2001) EGF-R Jeffrey, S. S., Rees, C. A., Pollack, J. R., Ross, D. T., signaling through Fyn kinase disrupts the function of in- Johnsen, H., Akslen, L. A., Fluge, O., Pergamenschikov, tegrin alpha6beta4 at hemidesmosomes: role in epithelial A., Williams, C., Zhu, S. X., Lonning, P. E., Borresen-Dale, cell migration and carcinoma invasion. J. Cell Biol. 155, A. L., Brown, P. O. and Botstein, D. (2000) Molecular 447-458. portraits of human breast tumours. Nature 406, 747-752. 21. Moro, L., Dolce, L., Cabodi, S., Bergatto, E., Boeri Erba, 5. Nielsen, T. O., Hsu, F. D., Jensen, K., Cheang, M., Karaca, E., Smeriglio, M., Turco, E., Retta, S. F., Giuffrida, M. G., G., Hu, Z., Hernandez-Boussard, T., Livasy, C., Cowan, Venturino, M., Godovac-Zimmermann, J., Conti, A., Schae- D., Dressler, L., Akslen, L. A., Ragaz, J., Gown, A. M., fer, E., Beguinot, L., Tacchetti, C., Gaggini, P., Silengo, L., Gilks, C. B., van de Rijn, M. and Perou, C. M. (2004) Tarone, G. and Defilippi, P. (2002) Integrin-induced epi- Immunohistochemical and clinical characterization of the dermal growth factor (EGF) receptor activation requires basal-like subtype of invasive breast carcinoma. Clin. c-Src and p130Cas and leads to phosphorylation of specif- Cancer Res. 10, 5367-5374. ic EGF receptor tyrosines. J. Biol. Chem. 277, 9405-9414. 6. Byers, S., Park, M., Sommers, C. and Seslar, S. (1994) 22. Mahabeleshwar, G. H., Feng, W., Reddy, K., Plow, E. F. Breast carcinoma: a collective disorder. Breast Cancer and Byzova, T. V. (2007) Mechanisms of integrin-vascular Res. Treat. 31, 203-215. endothelial growth factor receptor cross-activation in 7. Shaw, L. M. (1999) Integrin function in breast carcinoma angiogenesis. Circ. Res. 101, 570-580. progression. J. Mammary. Gland. Biol. Neoplasia. 4, 23. Somanath, P. R., Kandel, E. S., Hay, N. and Byzova, T. V. 367-376. (2007) Akt1 signaling regulates integrin activation, matrix 8. Aumailley, M., Pesch, M., Tunggal, L., Gaill, F. and recognition, and fibronectin assembly. J. Biol. Chem. 282, Fassler, R. (2000) Altered synthesis of laminin 1 and ab- 22964-22976. sence of basement membrane component deposition in 24. Schneller, M., Vuori, K. and Ruoslahti, E. (1997) Alphav- (beta)1 integrin-deficient embryoid bodies. J. Cell Sci. 113 beta3 integrin associates with activated insulin and PDGF Pt 2, 259-268. beta receptors and potentiates the biological activity of 9. Plow, E. F., Haas, T. A., Zhang, L., Loftus, J. and Smith, J. PDGF. EMBO J. 16, 5600-5607. W. (2000) Ligand binding to integrins. J. Biol. Chem. 275, 25. Borges, E., Jan, Y. and Ruoslahti, E. (2000) Platelet-derived 21785-21788. growth factor receptor beta and vascular endothelial 10. van der Flier, A. and Sonnenberg, A. (2001) Function and growth factor receptor 2 bind to the beta 3 integrin interactions of integrins. Cell Tissue. Res. 305, 285-298. through its extracellular domain. J. Biol. Chem. 275, 11. Aplin, A. E., Howe, A. K. and Juliano, R. L. (1999) Cell ad- 39867-39873. hesion molecules, signal transduction and cell growth. 26. Soldi, R., Mitola, S., Strasly, M., Defilippi, P., Tarone, G. Curr. Opin. Cell Biol. 11, 737-744. and Bussolino, F. (1999) Role of alphavbeta3 integrin in 12. Luo, B. H., Carman, C. V. and Springer, T. A. (2007) the activation of vascular endothelial growth factor re- Structural basis of integrin regulation and signaling. Annu. ceptor-2. EMBO J. 18, 882-892. Rev. Immunol. 25, 619-647. 27. Falcioni, R., Antonini, A., Nistico, P., Di Stefano, S., 13. Bryan, B. A. and D'Amore, P. A. (2007) What tangled Crescenzi, M., Natali, P. G. and Sacchi, A. (1997) Alpha 6 webs they weave: Rho-GTPase control of angiogenesis. beta 4 and alpha 6 beta 1 integrins associate with ErbB-2 Cell Mol. Life Sci. 64, 2053-2065. in human carcinoma cell lines. Exp. Cell Res. 236, 76-85. 14. Kanda, S., Kanetake, H. and Miyata, Y. (2007) Role of Src 28. Trusolino, L., Bertotti, A. and Comoglio, P. M. (2001) A in angiopoietin 1-induced capillary morphogenesis of en- signaling adapter function for alpha6beta4 integrin in the dothelial cells: effect of chronic hypoxia on Src inhibition control of HGF-dependent invasive growth. Cell 107, by PP2. Cell Signal 19, 472-480. 643-654. 15. Ridley, A. (2000) Rho GTPases. Integrating integrin 29. Santoro, M. M., Gaudino, G. and Marchisio, P. C. (2003) signaling. J. Cell Biol. 150, F107-109. The MSP receptor regulates alpha6beta4 and alpha3beta1 16. Schwartz, M. A. and Shattil, S. J. (2000) Signaling net- integrins via 14-3-3 proteins in keratinocyte migration. works linking integrins and rho family GTPases. Trends Dev. Cell 5, 257-271. Biochem. Sci. 25, 388-391. 30. Lipscomb, E. A. and Mercurio, A. M. (2005) Mobilization 17. Bertotti, A., Comoglio, P. M. and Trusolino, L. (2006) and activation of a signaling competent alpha6beta4in- Beta4 integrin activates a Shp2-Src signaling pathway that tegrin underlies its contribution to carcinoma progression. sustains HGF-induced anchorage-independent growth. J. Cancer Metastasis Rev. 24, 413-423. Cell Biol. 175, 993-1003. 31. Maile, L. A. and Clemmons, D. R. (2002) The alphaVbeta3 18. Klemke, R. L., Leng, J., Molander, R., Brooks, P. C., Vuori, integrin regulates insulin-like growth factor I (IGF-I) re- K. and Cheresh, D. A. (1998) CAS/Crk coupling serves as ceptor phosphorylation by altering the rate of recruitment a "molecular switch" for induction of cell migration. J. of the Src-homology 2-containing phosphotyrosine phos- Cell Biol. 140, 961-972. phatase-2 to the activated IGF-I receptor. Endocrinology 19. Collins, L. R., Ricketts, W. A., Yeh, L. and Cheresh, D. 143, 4259-4264. (1999) Bifurcation of cell migratory and proliferative sig- 32. Baron, W., Shattil, S. J. and ffrench-Constant, C. (2002)

316 BMB reports http://bmbreports.org Crosstalk between integrins and RTKs Young Hwa Soung, et al.

The oligodendrocyte precursor mitogen PDGF stimulates ing between alpha(6)beta(4) integrin and ErbB-2 receptor proliferation by activation of alpha(v)beta3 integrins. is required to promote phosphatidylinositol 3-kinase- EMBO J. 21, 1957-1966. dependent invasion. J. Biol. Chem. 275, 10604-10610. 33. Rabinovitz, I., Toker, A. and Mercurio, A. M. (1999) 48. Folgiero, V., Bachelder, R. E., Bon, G., Sacchi, A., Falcioni, Protein kinase C-dependent mobilization of the alpha R. and Mercurio, A. M. (2007) The alpha6beta4 integrin 6beta4 integrin from hemidesmosomes and its association can regulate ErbB-3 expression: implications for alpha6 with actin-rich cell protrusions drive the chemotactic mi- beta4 signaling and function. Cancer Res. 67, 1645-1652. gration of carcinoma cells. J. Cell Biol. 146, 1147-1160. 49. Gilcrease, M. Z., Zhou, X., Lu, X., Woodward, W. A., 34. Rabinovitz, I., Tsomo, L. and Mercurio, A. M. (2004) Pro- Hall, B. E. and Morrissey, P. J. (2009) Alpha6beta4 in- tein kinase C-alpha phosphorylation of specific serines in tegrin crosslinking induces EGFR clustering and promotes the connecting segment of the beta 4 integrin regulates EGF-mediated Rho activation in breast cancer. J. Exp. Clin. the dynamics of type II hemidesmosomes. Mol. Cell Biol. Cancer Res. 28, 67. 24, 4351-4360. 50. Chung, J., Yoon, S. O., Lipscomb, E. A. and Mercurio, A. 35. Germain, E. C., Santos, T. M. and Rabinovitz, I. (2009) M. (2004) The Met receptor and alpha 6 beta 4 integrin Phosphorylation of a novel site on the {beta}4 integrin at can function independently to promote carcinoma the trailing edge of migrating cells promotes hemi- invasion. J. Biol. Chem. 279, 32287-32293. desmosome disassembly. Mol. Biol. Cell 20, 56-67. 51. Meyer, T., Marshall, J. F. and Hart, I. R. (1998) Expression 36. Trusolino, L. and Comoglio, P. M. (2002) Scatter-factor of alphav integrins and vitronectin receptor identity in and semaphorin receptors: cell signalling for invasive breast cancer cells. Br. J. Cancer 77, 530-536. growth. Nat. Rev. Cancer 2, 289-300. 52. Wong, N. C., Mueller, B. M., Barbas, C. F., Ruminski, P., 37. Mercurio, A. M., Bachelder, R. E., Rabinovitz, I., O'Connor, Quaranta, V., Lin, E. C. and Smith, J. W. (1998) Alphav in- K. L., Tani, T. and Shaw, L. M. (2001) The metastatic tegrins mediate adhesion and migration of breast carcino- odyssey: the integrin connection. Surg. Oncol. Clin. N. ma cell lines. Clin. Exp. Metastasis. 16, 50-61. Am. 10, 313-328. 53. Brooks, P. C., Stromblad, S., Klemke, R., Visscher, D., 38. Nguyen, B. P., Ryan, M. C., Gil, S. G. and Carter, W. G. Sarkar, F. H. and Cheresh, D. A. (1995) Antiintegrin alpha (2000) Deposition of laminin 5 in epidermal wounds reg- v beta 3 blocks human breast cancer growth and angio- ulates integrin signaling and adhesion. Curr. Opin. Cell genesis in human skin. J. Clin. Invest. 96, 1815-1822. Biol. 12, 554-562. 54. Gramoun, A., Shorey, S., Bashutski, J. D., Dixon, S. J., 39. Mercurio, A. M., Bachelder, R. E., Bates, R. C. and Chung, Sims, S. M., Heersche, J. N. and Manolson, M. F. (2007) J. (2004) Autocrine signaling in carcinoma: VEGF and the Effects of Vitaxin, a novel therapeutic in trial for metastatic alpha6beta4 integrin. Semin. Cancer Biol. 14, 115-122. bone tumors, on osteoclast functions in vitro. J. Cell 40. Chung, J. and Mercurio, A. M. (2004) Contributions of the Biochem. 102, 341-352. alpha6 integrins to breast carcinoma survival and pro- 55. Eliceiri, B. P. (2001) Integrin and growth factor receptor gression. Mol. Cells 17, 203-209. crosstalk. Circ. Res. 89, 1104-1110. 41. Mercurio, A. M. and Rabinovitz, I. (2001) Towards a me- 56. Tuck, A. B., Elliott, B. E., Hota, C., Tremblay, E. and chanistic understanding of tumor invasion--lessons from Chambers, A. F. (2000) Osteopontin-induced, integrin- the alpha6beta 4 integrin. Semin. Cancer Biol. 11, 129- dependent migration of human mammary epithelial cells 141. involves activation of the hepatocyte growth factor re- 42. Chung, J., Bachelder, R. E., Lipscomb, E. A., Shaw, L. M. ceptor (Met). J. Cell Biochem. 78, 465-475. and Mercurio, A. M. (2002) Integrin (alpha 6 beta 4) regu- 57. White, D. E. and Muller, W. J. (2007) Multifaceted roles of lation of eIF-4E activity and VEGF translation: a survival integrins in breast cancer metastasis. J. Mammary. Gland. mechanism for carcinoma cells. J. Cell Biol. 158, 165- Biol. Neoplasia. 12, 135-142. 174. 58. Colognato, H., Baron, W., Avellana-Adalid, V., Relvas, J. 43. Mercurio, A. M., Rabinovitz, I. and Shaw, L. M. (2001) B., Baron-Van Evercooren, A., Georges-Labouesse, E. and The alpha 6 beta 4 integrin and epithelial cell migration. ffrench-Constant, C. (2002) CNS integrins switch growth Curr. Opin. Cell Biol. 13, 541-545. factor signalling to promote target-dependent survival. 44. Head, B. P., Patel, H. H., Roth, D. M., Murray, F., Nat. Cell Biol. 4, 833-841. Swaney, J. S., Niesman, I. R., Farquhar, M. G. and Insel, 59. Somanath, P. R., Malinin, N. L. and Byzova, T. V. (2009) P. A. (2006) Microtubules and actin microfilaments regu- Cooperation between integrin alphavbeta3 and VEGFR2 late lipid raft/caveolae localization of adenylyl cyclase sig- in angiogenesis. Angiogenesis 12, 177-185. naling components. J. Biol. Chem. 281, 26391-26399. 60. Phillips, D. R., Prasad, K. S., Manganello, J., Bao, M. and 45. de Laurentiis, A., Donovan, L. and Arcaro, A. (2007) Lipid Nannizzi-Alaimo, L. (2001) Integrin tyrosine phosphor- rafts and caveolae in signaling by growth factor receptors. ylation in platelet signaling. Curr. Opin. Cell Biol. 13, Open Biochem. J. 1, 12-32. 546-554. 46. Guo, W., Pylayeva, Y., Pepe, A., Yoshioka, T., Muller, W. 61. Mori, S., Wu, C. Y., Yamaji, S., Saegusa, J., Shi, B., Ma, J., Inghirami, G. and Giancotti, F. G. (2006) Beta 4 in- Z., Kuwabara, Y., Lam, K. S., Isseroff, R. R., Takada, Y. K. tegrin amplifies ErbB2 signaling to promote mammary and Takada, Y. (2008) Direct binding of integrin alphavbe- tumorigenesis. Cell 126, 489-502. ta3 to FGF1 plays a role in FGF1 signaling. J. Biol. Chem. 47. Gambaletta, D., Marchetti, A., Benedetti, L., Mercurio, A. 283, 18066-18075. M., Sacchi, A. and Falcioni, R. (2000) Cooperative signal- 62. Danen, E. H. and Yamada, K. M. (2001) Fibronectin, in- http://bmbreports.org BMB reports 317 Crosstalk between integrins and RTKs Young Hwa Soung, et al.

tegrins, and growth control. J. Cell Physiol. 189, 1-13. ssolino, F. (2005) Stable interaction between alpha5beta1 63. Nista, A., Leonetti, C., Bernardini, G., Mattioni, M. and integrin and Tie2 tyrosine kinase receptor regulates endo- Santoni, A. (1997) Functional role of alpha4beta1 and al- thelial cell response to Ang-1. J. Cell Biol. 170, 993-1004. pha5beta1 integrin fibronectin receptors expressed on 68. Zhang, X., Groopman, J. E. and Wang, J. F. (2005) Ex- adriamycin-resistant MCF-7 human mammary carcinoma tracellular matrix regulates endothelial functions through cells. Int. J. Cancer 72, 133-141. interaction of VEGFR-3 and integrin alpha5beta1. J. Cell 64. Morozevich, G., Kozlova, N., Cheglakov, I., Ushakova, N. Physiol. 202, 205-214. and Berman, A. (2009) Integrin alpha5beta1 controls in- 69. Lee, J. W. and Juliano, R. L. (2002) The alpha5beta1 invasion of human breast carcinoma cells by direct and integrin selectively enhances epidermal growth factor sig- direct modulation of MMP-2 collagenase activity. Cell naling to the phosphatidylinositol-3-kinase/Akt pathway in Cycle 8, 2219-2225. intestinal epithelial cells. Biochim. Biophys. Acta. 1542, 65. Jia, Y., Zeng, Z. Z., Markwart, S. M., Rockwood, K. F., 23-31. Ignatoski, K. M., Ethier, S. P. and Livant, D. L. (2004) 70. Rahman, S., Patel, Y., Murray, J., Patel, K. V., Sumathipa- Integrin fibronectin receptors in matrix metalloproteinase- la, R., Sobel, M. and Wijelath, E. S. (2005) Novel hep- 1-dependent invasion by breast cancer and mammary epi- atocyte growth factor (HGF) binding domains on fi- thelial cells. Cancer Res. 64, 8674-8681. bronectin and vitronectin coordinate a distinct and ampli- 66. Liu, Y., Pixley, R., Fusaro, M., Godoy, G., Kim, E., fied Met-integrin induced signalling pathway in endothe- Bromberg, M. E. and Colman, R. W. (2009) Cleaved lial cells. BMC. Cell Biol. 6, 8. high-molecular-weight kininogen and its domain 5 inhibit 71. Bell, L. N., Cai, L., Johnstone, B. H., Traktuev, D. O., migration and invasion of human prostate cancer cells March, K. L. and Considine, R. V. (2008) A central role for through the epidermal growth factor receptor pathway. hepatocyte growth factor in adipose tissue angiogenesis. Oncogene 28, 2756-2765. Am. J. Physiol. Endocrinol. Metab. 294, E336-344. 67. Cascone, I., Napione, L., Maniero, F., Serini, G. and Bu-

318 BMB reports http://bmbreports.org