SH3PXD2A (SH3 and PX domains 2A)

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Citation Li, Carman Man-Chung and Tyler Jacks. “SH3PXD2A (SH3 and PX Domains 2A).” Atlas of Genetics and Cytogenetics in Oncology and Haematology 6 (2016): 326-330 © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

As Published http://dx.doi.org/10.4267/2042/62941

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Citable link http://hdl.handle.net/1721.1/116550

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SH3PXD2A (SH3 and PX domains 2A) Carman Man-Chung Li, Tyler Jacks David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. [email protected]

Published in Atlas Database: August 2015 Online updated version : http://AtlasGeneticsOncology.org/Genes/SH3PXD2AID45995ch10q24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62941/08-2015-SH3PXD2AID45995ch10q24.pdf DOI: 10.4267/2042/62941 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Transcription The full-length SH3PXD2A transcript is 11264 nt in The TKS5 protein, encoded by the gene length. Multiple TKS5 isoforms arise as a result of SH3PXD2A, is a scaffolding protein essential for the alternative mRNA splicing involving exons 7 and formation of podosomes and invadopodia in 10, and alternative use of transcription start sites. untransformed cells and cancer cells, respectively. Podosomes and invadopodia (which collectively are Protein termed invadosomes) are actin-rich cellular protrusions capable of secreting proteolytic enzymes Description that can degrade the extracellular matrix. These The full-length SH3PXD2A transcript (TKS5- structures are thought to regulate cellular migration LONG or TKS5-ALPHA) is transcribed from a and invasion, as well as adhesion and the release of promoter upstream of exon 1 and is translated into a growth factors. In the context of cancer, TKS5- 150 kDa protein that contains a Phox-homology dependent invadopodia activity has been shown to (PX) domain in the N-terminus and five Src play important roles in tumor growth and metastasis homology 3 (SH3) domains in the C-terminus. The in various cancer types. Multiple isoforms of TKS5 shorter isoforms that arise from downstream exist due to alternative mRNA splicing and promoter transcription start sites lack the PX domain but retain usage. the five SH3 domains. Because the PX domain is Keywords required for binding to the cell membrane, full- SH3PXD2A; TKS5; podosomes; invadopodia; length TKS5 is able to localize to invadosome foci metastasis. but the short isoforms cannot. Identity Expression Other names: TKS5, FISH, SH3MD1, KIAA0418 TKS5 expression is detected in many tissue types, including brain, lung, liver, heart, skeletal muscles, HGNC (Hugo): SH3PXD2A and, kidneys, but was low in spleen and absent in Location: 10q24.33 testis (Lock et al, 1998). Tks5 has also been detected in many cell types, including macrophages, DNA/RNA myoblasts, neural crest cells, osteoblasts, and neurons (Burger et al., 2011; Thompson et al., 2008; Description Murphy et al., 2011; Oikawa et al., 2012; Santiago- The SH3PXD2A gene is located on chromosome 10 Medina et al. 2015). (10q24.33). It contains 15 exons.

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The SH3PXD2A locus encodes multiple TKS5 isoforms as a result of alternative splicing at exons 7 and 10 as well as alternative promoter usage. Genomic information was obtained from the UCSC genome browser (http://genome.ucsc.edu/). Short-form Tks5 (Tks5-short and Tks5-beta) have been reported by Li et al. (2013) and Cejudo-Martin et al. (2014).

Localisation 2008). At the cell membrane, TKS5 is thought to interact with multiple components of invadosomes Cytoplasmic and at invadosome foci. either directly or indirectly, and thereby mediates Function invadosome formation and maturation (Sharma et TKS5 was initially identified as a substrate for SRC al., 2013). These interacting partners includes (Lock et al., 1998), and was subsequently shown to adaptor proteins and actin regulatory proteins, such play a critical role in invadosome formation in as NCK1, NCK2, GRB2, CTTN (Cortactin), WASL multiple cell types (Courtneidge, 2011; Murphy and (N-WASP), ACTR2/ACTR3 (Arp2/3) complex, and Courtneidge, 2011; Paz et al., 2013). ARHGAP35 (p190RhoGAP) (Crimaldi et al., 2009; Full-length TKS5 functions as an adaptor for Oikawa et al., 2008; Stylli et al., 2009). TKS5 also recruiting other proteins to the cell membrane for interacts with NOXA1 and CYBA (p22phox), which invadosome formation. are components of the NADPH oxidase complex, The recruitment of TKS5 to the cell membrane and thereby promotes reactive oxygen species (ROS) depends on its PX domain and phosphorylation by production by NOX enzymes at invadosomes (Diaz Src (Abram et al., 2003). It has been proposed that et al., 2009; Gianni et al., 2010; 2009). ROS have phosphorylation of TKS5 releases its PX domain been shown to facilitate invadosome formation by from intramolecular interaction and allows TKS5 to maintaining or amplifying the phosphorylation of bind to cell membrane phosphatidylinositol lipids, TKS5. As such, TKS5 is thought to promote such as phosphatidylinositol-3,4-bisphosphate invadosome formation via ROS in a positive (PI(3,4)P2) (Abram et al., 2003; Oikawa et al., feedback loop.

The full-length TKS5 mRNA encodes a protein that contains a PX domain and five SH3 domains, as well as proline-rich regions (PxxP) and Src phosphorylation sites (Y). The various short isoforms lack the PX domain.

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Finally, TKS5 has also been shown to interact with Homology members of the ADAM family metalloproteases, specifically ADAM12, ADAM15, ADAM19 TKS5 is homologous to SH3PXD2B (TKS4), (Abram et al., 2003). It is believed that Tks5 recruits another adaptor protein that functions as a Src theses proteases to the invadosome foci for substrate and promotes invadosome function processing growth factors and regulating cell (Buschman et al, 2009). TKS4 contains a PX domain motility. For example, ADAM12 has been shown to at the N-terminus and four SH3 domains in the C- promote ectodomain shedding of HBEGF (heparin- terminus. binding EGF-like growth factor) and enhance invadopodia formation in cancer cells (Diaz et al., Implicated in 2013). In the context of cancer, TKS5-dependent formation Breast cancer of invadopodia is thought to promote metastasis by TKS5 expression is increased in human primary mediating local tumor invasion and intravasation at breast tumors compared to normal tissues, and is the primary site, as well as extravasation and further increased in metastases (Stylli et al., 2014). colonization at the distant site (Murphy and TKS5 is required for invadopodia formation in Courtneidge, 2011; Paz et al., 2014). breast cancer cells (Seals et al, 2005). In the context of normal development, TKS5- TKS5-dependent invadopodia have been shown to depedent podosomes are important for mediating promote tumor growth in a transplantation setting, cell migration during embryogenesis. Knockdown of cancer cell intravasation and extravasation, and Tks5 in zebrafish led to impaired dorsal-ventral metastasis formation (Eckert et al., 2011; migration of neural crest cells and defective Gligorijevic et al., 2012; Leong et al., 2014; Blouw craniofacial structures and pigmentation (Murphy et et al., 2015). al., 2011). Similarly, genetic deletion of Tks5 in Expression of full-length TKS5 in human breast mice led to complete cleft of the secondary palate tumors correlated with poor prognosis (Blouw et al., and neonatal death (Cejudo-Martin et al., 2014). In 2015). addition, study in Xenopus showed that Tks5- Lung cancer dependent podosomes are also required for the TKS5 expression is increased in human lung tumors migration of neuronal growth cones (Santiago- compared to normal tissues (Stylli et al., 2014). Full- Medina et al., 2015). length Tks5 is required for metastasis in a mouse While most studies have focused on full-length model of lung cancer (Li et al., 2013). Furthermore, TKS5, shorter isoforms of TKS5 that lack the PX higher expression of full-length TKKS5 relative to domain have been reported (Lock et al, 1998; Li et short-form TKS5 correlated with poor survival of al., 2013; Cejudo-Martin et al., 2014). early-stage lung adenocarcinoma patients (Li et al., There are few reports on the functions of these short 2013). isoforms. Experiments in mouse lung cancer cell lines showed Melanoma that overexpression of a short isoform (Tks5-short) TKS5 is required for invadopodia formation in suppressed invadopodia function by disrupting the melanoma cells (Seals et al, 2005). stability of invadopodia (Li et al., 2013). In addition, overexpression of a short-form equivalent protein, Prostate cancer ΔPX-Tks5, in Xenopus neural crest cells inhibited TKS5 expression is increased in human prostate invadosome functions and impaired motoneuron tumors compared to normal tissues, and is required axon extension into the peripheral myotomal tissue for invadopodia function in prostate cancer cells in Xenopus embryos (Santiago-Medina et al., 2015). (Stylli et al., 2014; Burger et al., 2014). These data suggest that the short forms of TKS5 can Gliomas function as negative regulators of invadosomes. At the mRNA level, the transcription of full-length TKS5 expression correlates with poor survival of Tks5 has been shown to be synergistically inhibited glioma patients (Stylli et al., 2011). by the developmental regulators NKX2-1, FOXA2, Colon Cancer and CDX2 in lung adenocarcinoma (Li et al., 2015). Furthermore, TKS5 has been shown to be a target of TKS5 expression is increased in human colon the microRNA mir200-c (Sundararajan et al., 2015). tumors compared to normal tissues (Stylli et al., In terms of protein stability and abundance, the full- 2014). length isoform of TKS5 is positively Alzeimer disease regulated by Src, while the short isoform (TKS5- KS5 and ADAM12 have been proposed to mediate beta) is negatively regulated by Src (Cejudo-Martin the toxicity of amyloid-β peptide (Aβ), which is a et al. 2014). potential cause of Alzheimer's disease as it has been

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shown to mediate neurodegenerative alterations that formation is involved in intravasation and lung metastasis of are associated with amyloid plaques (Malinin et al., mammary tumors J Cell Sci 2012 Feb 1;125(Pt 3):724-34 2005; Harold et al., 2007). Harold D, Jehu L, Turic D, Hollingworth P, Moore P, Summerhayes P, Moskvina V, Foy C, Archer N, Hamilton BA, Lovestone S, Powell J, Brayne C, Rubinsztein DC, References Jones L, O'Donovan MC, Owen MJ, Williams J. Interaction Abram CL, Seals DF, Pass I, Salinsky D, Maurer L, Roth between the ADAM12 and SH3MD1 genes may confer TM, Courtneidge SA. The adaptor protein fish associates susceptibility to late-onset Alzheimer's disease Am J Med with members of the ADAMs family and localizes to Genet B Neuropsychiatr Genet 2007 Jun 5;144B(4):448-52 podosomes of Src-transformed cells. J Biol Chem. 2003 Leong HS, Robertson AE, Stoletov K, Leith SJ, Chin CA, May 9;278(19):16844-51 Chien AE, Hague MN, Ablack A, Carmine-Simmen K, Blouw B, Patel M, Iizuka S, Abdullah C, You WK, Huang X, McPherson VA, Postenka CO, Turley EA, Courtneidge SA, Li JL, Diaz B, Stallcup WB, Courtneidge SA. The Chambers AF, Lewis JD. Invadopodia are required for invadopodia scaffold protein Tks5 is required for the growth cancer cell extravasation and are a therapeutic target for of human breast cancer cells in vitro and in vivo. PLoS One. metastasis Cell Rep 2014 Sep 11;8(5):1558-70 2015;10(3):e0121003 Li CM, Chen G, Dayton TL, Kim-Kiselak C, Hoersch S, Burger KL, Davis AL, Isom S, Mishra N, Seals DF. The Whittaker CA, Bronson RT, Beer DG, Winslow MM, Jacks podosome marker protein Tks5 regulates macrophage T. Differential Tks5 isoform expression contributes to invasive behavior. Cytoskeleton (Hoboken). 2011 metastatic invasion of lung adenocarcinoma Genes Dev Dec;68(12):694-711 2013 Jul 15;27(14):1557-67 Burger KL, Learman BS, Boucherle AK, Sirintrapun SJ, Li CM, Gocheva V, Oudin MJ, Bhutkar A, Wang SY, Date Isom S, Díaz B, Courtneidge SA, Seals DF. Src-dependent SR, Ng SR, Whittaker CA, Bronson RT, Snyder EL, Gertler Tks5 phosphorylation regulates invadopodia-associated FB, Jacks T. Foxa2 and Cdx2 cooperate with Nkx2-1 to invasion in prostate cancer cells. Prostate. 2014 inhibit lung adenocarcinoma metastasis Genes Dev 2015 Feb;74(2):134-48 Sep 1;29(17):1850-62 Buschman MD, Bromann PA, Cejudo-Martin P, Wen F, Lock P, Abram CL, Gibson T, Courtneidge SA. A new Pass I, Courtneidge SA. The novel adaptor protein Tks4 method for isolating tyrosine kinase substrates used to (SH3PXD2B) is required for functional podosome formation. identify fish, an SH3 and PX domain-containing protein, and Mol Biol Cell. 2009 Mar;20(5):1302-11 Src substrate EMBO J 1998 Aug 3;17(15):4346-57 Cejudo-Martin P, Yuen A, Vlahovich N, Lock P, Courtneidge Malinin NL, Wright S, Seubert P, Schenk D, Griswold- SA, Díaz B. Genetic disruption of the sh3pxd2a gene Prenner I. Amyloid-beta neurotoxicity is mediated by FISH reveals an essential role in mouse development and the adapter protein and ADAM12 metalloprotease activity Proc existence of a novel isoform of tks5. PLoS One. Natl Acad Sci U S A 2005 Feb 22;102(8):3058-63 2014;9(9):e107674 Murphy DA, Courtneidge SA. The 'ins' and 'outs' of Courtneidge SA. Cell migration and invasion in human podosomes and invadopodia: characteristics, formation disease: the Tks adaptor proteins. 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maturation, but not initiation, in breast carcinoma cells Curr Sundararajan V, Gengenbacher N, Stemmler MP, Biol 2013 Nov 4;23(21):2079-89 Kleemann JA, Brabletz T, Brabletz S. The ZEB1/miR-200c feedback loop regulates invasion via actin interacting Stylli SS, I ST, Kaye AH, Lock P. Prognostic significance of proteins MYLK and TKS5 Oncotarget 2015 Sep Tks5 expression in gliomas J Clin Neurosci 2012 29;6(29):27083-96 Mar;19(3):436-42 Thompson O, Kleino I, Crimaldi L, Gimona M, Saksela K, Stylli SS, Luwor RB, Kaye AH, I ST, Hovens CM, Lock P. Winder SJ. Dystroglycan, Tks5 and Src mediated assembly Expression of the adaptor protein Tks5 in human cancer: of podosomes in myoblasts PLoS One 2008;3(11):e3638 prognostic potential Oncol Rep 2014 Sep;32(3):989-1002 Stylli SS, Stacey TT, Verhagen AM, Xu SS, Pass I, This article should be referenced as such: Courtneidge SA, Lock P. Nck adaptor proteins link Tks5 to Li CMC, Jacks T. SH3PXD2A (SH3 and PX domains 2A). invadopodia actin regulation and ECM degradation J Cell Atlas Genet Cytogenet Oncol Haematol. 2016; Sci 2009 Aug 1;122(Pt 15):2727-40 20(6):326-330.

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