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Regulation of the Akt Kinase by Interacting Proteins Oncogene (2005) 24, 7401–7409 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc Regulation of the Akt kinase by interacting proteins Keyong Du1 and Philip N Tsichlis*,1 1Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111, USA Ten years ago, it was observed that the Akt kinase revolutionized our understanding of cell function at is activated by phosphorylation via a phosphoinositide the molecular level.These technologies also allowed 3-kinase (PI-3K)-dependent process. This discovery gene- the identification of a large array of protein–protein rated enormous interest because it provided a link between interaction motifs that facilitate our understanding of PI-3K, an enzyme known to play a critical role in cellular signal transduction by providing clues on the potential physiology, and its downstream targets. Subsequently, it function of novel signaling proteins (Barnouin, 2004; was shown that the activity of the core components of the Miller and Stagljar, 2004). ‘PI-3K/Akt pathway’ is modulated by a complex network Akt1, also known as protein kinase Ba (PKBa) of regulatory proteins and pathways. Some of the Akt- (Bellacosa et al., 1991; Coffer and Woodgett, 1991; binding partners modulate its activation by external Jones et al., 1991), is the founding member of a protein signals by interacting with different domains of the Akt kinase family composed of three members, Akt1, Akt2, protein. This review focuses on the Akt interacting and Akt3.Akt family members regulate a diverse proteins and the mechanisms by which they regulate Akt array of cellular functions, including apoptosis, cellular activation. proliferation, differentiation, and intermediary meta- Oncogene (2005) 24, 7401–7409. doi:10.1038/sj.onc.1209099 bolism (Chan et al., 1999). Akt activation depends on PtdIns-3,4,5-P3, and to a lesser extent on PtdIns-3,4-P2, Keywords: Akt; PKB; protein–protein interaction; both of which are products of phosphoinositide 3-kinase phosphoinositide 3-kinase (PI-3K) (Franke et al., 1995). The interaction of PtdIns- 3,4,5-P3 with the Pleckstrin homology (PH) domain of Akt promotes the translocation of Akt to the plasma membrane, where it undergoes phosphorylation at Introduction two sites, one in the activation loop (Thr308) and the other in the carboxy-terminal (C-terminal) tail Intercellular and intracellular communications depend (Ser473).Phosphorylation at Ser473 appears to precede to a significant degree on the interaction between and facilitate phosphorylation at Thr308 (Sarbassov different signaling proteins.Such interactions may be et al., 2005 and references therein). The kinase that responsible for the initiation and progression of a phosphorylates Akt at Thr308 is PI-3K-dependent variety of cellular processes.For example, protein– kinase 1 (PDK1) (Chan et al., 1999). The kinase that protein interactions may induce conformational changes phosphorylates Akt at Ser473 (PDK2) had been elusive that stabilize, destabilize, or alter the enzymatic proper- for many years.Recent studies revealed that in 293T ties of the interacting partners (Goh et al., 2004). cells and several carcinoma cell lines, Akt phosphory- Protein–protein interactions may also contribute to the lation at this site depends on a complex that contains formation of large molecular complexes that allow the the mammalian target of rapamycin (mTOR), GbL, coordinate response of multiple molecules to incoming and rictor (Sarbassov et al., 2005). Earlier studies had signals (Stagljar, 2003).Finally, some proteins may shown that several additional kinases, including ILK-1, function as anchors that allow the association of their PDK1, Akt itself, and perhaps other members of the binding partners with certain cellular structures or may AGC kinase family, as well as DNA-PKcs, may have the facilitate the transport of their partners between cellular potential to phosphorylate Akt at this site (Chan and compartments (Fowler and Alarid, 2004).To accom- Tsichlis, 2001; Dong and Liu, 2005).Although the role plish these diverse outcomes, interacting proteins bind of the rictor–mTOR complex in the phosphorylation of each other either constitutively or in a signal-dependent Akt at Ser473 is beyond doubt, the potential involve- manner, and modify the activities of their interacting ment of these kinases in this process in some cells partners by providing either an adaptor or an enzymatic responding to specific signals has not been excluded function.The realization that protein–protein inter- today.Phosphorylated Akt may translocate from the actions play a critical role in cell signaling led to plasma membrane to the cytosol or the nucleus (Meier the establishment of technologies that allowed the et al., 1997; Meier and Hemmings, 1999). Activated Akt identification of networks of interacting proteins and ultimately undergoes dephosphorylation by phospha- tases and returns to the inactive state (Meier et al., 1998) *Correspondence: PN Tsichlis; E-mail: [email protected] (Figure 1). Regulation of the Akt kinase K Du and PN Tsichlis 7402 External Signals. Receptor P P P P P P P P P P P P P P P P P Tyr376 P P P PDK1 P Thr308 P PIP3 P P Tyr373 PI3K P P P P Ser241 P Akt P Ser473 Inositol Poly phosphate phosphatases Thr308 P Akt P Thr308 Ser473 P Akt Thr308 P Akt Ser473 Ser473 Thr308 Akt nucleus Ser473 Figure 1 Core components of the PI-3K/Akt activation pathway.Extracellular signals activate PI-3K, which in turn promotes the synthesis of D3 PPIs.Akt binds to the plasma membrane-associated D3 PPIs via its PH domain, and undergoes phosphorylation at Ser473 (by PDK2) and Thr308 (by PDK1).Phosphorylation at Ser473 precedes and facilitates phosphorylation at Thr308.Activated Akt translocates from the plasma membrane to the cytosol or to the nucleus, where it phosphorylates a wide array of downstream effector proteins.Signal termination via D3 PPI hydrolysis is mediated by several inositol polyphosphate phosphatases, including PTEN, SHIP, and SHIP2.The activation cycle ends with dephosphorylation of Akt by protein phosphatases.Akt interacting proteins modulate the activity of the PI-3K/Akt pathway by interacting with different domains of the Akt protein Given the functional importance of Akt, the search Thr308 Ser473 for the identification of its binding partners has been Akt1 PH Kinase Domain C-Tail intense.Proteins interacting with Akt, and other TCL1 Cdc37/HSP90 CTMP kinases, include kinase substrates and kinase regulators. JIP1 TRB3 APE In this review, we will focus on the interaction of Akt Grb10 APPL1 Src with regulatory molecules.For the sake of clarity, Akt RasGAP Keratin 10 ArgBP2γ interacting proteins will be grouped based on the Akt Prohibitin2 domain they interact with (Figure 2). PDK1* Figure 2 Interacting proteins bind specifically to different domains of Akt and either promote or inhibit Akt activation. Proteins interacting with the PH domain of Akt Linear diagram of Akt illustrating the domain architecture of the protein.Akt interacting partners are listed under the domain they interact with.*The interaction of PDK1 with The Akt C-tail is The PH domain of Akt binds D3 PPIs and promotes the supported by a host of experimental data, but it has not been translocation of the kinase to the plasma membrane, a formally demonstrated process that is critical for Akt activation (Chan et al., 1999).However, the PH domain may also interact with Akt regulatory proteins.The earliest observation that encodes a 14-kDa protein whose crystal structure the PH domain of Akt functions as a protein–protein suggests that it may be involved in molecular transport, interaction motif was presented in a paper showing that a function that may be relevant to its role in the Akt oligomerizes and that oligomerization is PH regulation of the Akt kinase (Petock et al., 2002). The domain-dependent (Datta et al., 1995). Tcl1 gene is the founding member of a gene family that includes Tcl1 itself, MTCP-1, located on chromosome Xq28 (Gritti et al., 1997) and Tcl1b, located together Tcl1 and other members of the Tcl1 protein family with Tcl1, on chromosome 14q32.1 (Hallas et al., 1999; The Tcl1 oncogene on chromosome 14q32.1 is activated Pekarsky et al., 1999). The latter is represented by at by chromosomal inversion or translocation ((Inv(14) least five homologs in the mouse (Hallas et al., 1999). All (q11;q32) and t(14; 14) (q11;q32) or t(7; 14) (q35;q32)) three genes have been shown to be involved in the in human T-cell leukemia (Virgilio et al., 1994). Tcl1 induction of different forms of human T-cell leukemia Oncogene Regulation of the Akt kinase K Du and PN Tsichlis 7403 (Teitell, 2005).Moreover, Tcl1 and MTCP1 have been of Tcl1.This illustrates that the interaction of Akt and shown to induce lymphoid tumors when overexpressed Tcl1 may have provided clues for the design of a in transgenic mice (Gritti et al., 1998; Virgilio et al., molecule that inhibits Akt by a wide range of signals. 1998). Tcl1 and Tcl1b are expressed normally in early T-cell progenitors, in pre-B, and in immature lgM- JNK interacting protein 1 (JIP1) expressing B cells (Pekarsky et al., 1999, 2004; Teitell, 2005). MTCP1 encodes 8- and 13-kDa proteins.Expres- JIP1 is a 660 amino-acid protein (707 amino acids (aa) sion of the 13-kDa isoform has been detected only in for JIP1b), which is involved in the assembly of T cells with a t(X;14) translocation (Madani et al., signaling complexes that contain JNK, MKK7, and 1996). MLK3 and is required for JNK activation (Yasuda All three Tcl1 family members interact with Akt1 and et al., 1999; Whitmarsh et al., 2001). It was recently Akt2.However, only Tcl1 interacts with all Akt shown that JIP1 also interacts specifically with the isoforms, including Akt3 (Laine et al., 2002).
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