| Structural highlights
Disease
[FAK2_HUMAN] Note=Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer.[1] [2] [3] [4] [5] [6] [7]
Function
[FAK2_HUMAN] Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2.[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [PAXI_CHICK] Cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix (focal adhesion). Binds in vitro to vinculin as well as to the SH3 domain of c-SRC and, when tyrosine phosphorylated, to the SH2 domain of v-CRK.
Publication Abstract from PubMed
Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase (FAK) subfamily of cytoplasmic tyrosine kinases. The C-terminal Pyk2 focal adhesion-targeting (Pyk2-FAT) domain binds to paxillin, an adhesion molecule. Paxillin has five leucine-aspartate (LD) motifs (LD1-LD5). Here, we show that the second LD motif of paxillin, LD2, interacts with Pyk2-FAT, similar to the known Pyk2-FAT/LD4 interaction. Both LD motifs can target two ligand-binding sites on Pyk2-FAT. Interestingly, they also share similar binding affinity for Pyk2-FAT with preferential association to one site relative to the other. Nevertheless, the LD2-LD4 region of paxillin (paxillin133-290) binds to Pyk2-FAT as a 1:1 complex. However, our data suggests that the Pyk2-FAT and paxillin complex is dynamic and it appears to be a mixture of two distinct conformations of paxillin which almost equally compete for Pyk2-FAT binding. These studies provide insight into the underlying selectivity of paxillin for Pyk2 and FAK which may influence the differing behavior of these two closely-related kinases in focal adhesion sites.
Structural and mechanistic insights into the interaction between Pyk2 and Paxillin LD motifs.,Vanarotti MS, Miller DJ, Guibao CD, Nourse A, Zheng JJ J Mol Biol. 2014 Aug 28. pii: S0022-2836(14)00457-4. doi:, 10.1016/j.jmb.2014.08.014. PMID:25174335[33]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Roberts WG, Ung E, Whalen P, Cooper B, Hulford C, Autry C, Richter D, Emerson E, Lin J, Kath J, Coleman K, Yao L, Martinez-Alsina L, Lorenzen M, Berliner M, Luzzio M, Patel N, Schmitt E, LaGreca S, Jani J, Wessel M, Marr E, Griffor M, Vajdos F. Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res. 2008 Mar 15;68(6):1935-44. PMID:18339875 doi:68/6/1935
- ↑ Sun CK, Man K, Ng KT, Ho JW, Lim ZX, Cheng Q, Lo CM, Poon RT, Fan ST. Proline-rich tyrosine kinase 2 (Pyk2) promotes proliferation and invasiveness of hepatocellular carcinoma cells through c-Src/ERK activation. Carcinogenesis. 2008 Nov;29(11):2096-105. doi: 10.1093/carcin/bgn203. Epub 2008, Sep 1. PMID:18765415 doi:10.1093/carcin/bgn203
- ↑ Allen JG, Lee MR, Han CY, Scherrer J, Flynn S, Boucher C, Zhao H, O'Connor AB, Roveto P, Bauer D, Graceffa R, Richards WG, Babij P. Identification of small molecule inhibitors of proline-rich tyrosine kinase 2 (Pyk2) with osteogenic activity in osteoblast cells. Bioorg Med Chem Lett. 2009 Sep 1;19(17):4924-8. doi: 10.1016/j.bmcl.2009.07.084. , Epub 2009 Jul 22. PMID:19648005 doi:10.1016/j.bmcl.2009.07.084
- ↑ Sun CK, Ng KT, Lim ZX, Cheng Q, Lo CM, Poon RT, Man K, Wong N, Fan ST. Proline-rich tyrosine kinase 2 (Pyk2) promotes cell motility of hepatocellular carcinoma through induction of epithelial to mesenchymal transition. PLoS One. 2011 Apr 20;6(4):e18878. doi: 10.1371/journal.pone.0018878. PMID:21533080 doi:10.1371/journal.pone.0018878
- ↑ Lipinski CA, Loftus JC. Targeting Pyk2 for therapeutic intervention. Expert Opin Ther Targets. 2010 Jan;14(1):95-108. doi: 10.1517/14728220903473194. PMID:20001213 doi:10.1517/14728220903473194
- ↑ Walker DP, Zawistoski MP, McGlynn MA, Li JC, Kung DW, Bonnette PC, Baumann A, Buckbinder L, Houser JA, Boer J, Mistry A, Han S, Xing L, Guzman-Perez A. Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity. Bioorg Med Chem Lett. 2009 Jun 15;19(12):3253-8. Epub 2009 Apr 24. PMID:19428251 doi:10.1016/j.bmcl.2009.04.093
- ↑ Han S, Mistry A, Chang JS, Cunningham D, Griffor M, Bonnette PC, Wang H, Chrunyk BA, Aspnes GE, Walker DP, Brosius AD, Buckbinder L. Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique (DFG-out) conformation and enables inhibitor design. J Biol Chem. 2009 May 8;284(19):13193-201. Epub 2009 Feb 25. PMID:19244237 doi:10.1074/jbc.M809038200
- ↑ Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, Plowman GD, Rudy B, Schlessinger J. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature. 1995 Aug 31;376(6543):737-45. PMID:7544443 doi:http://dx.doi.org/10.1038/376737a0
- ↑ Dikic I, Tokiwa G, Lev S, Courtneidge SA, Schlessinger J. A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature. 1996 Oct 10;383(6600):547-50. PMID:8849729 doi:10.1038/383547a0
- ↑ Tokiwa G, Dikic I, Lev S, Schlessinger J. Activation of Pyk2 by stress signals and coupling with JNK signaling pathway. Science. 1996 Aug 9;273(5276):792-4. PMID:8670418
- ↑ Andreev J, Simon JP, Sabatini DD, Kam J, Plowman G, Randazzo PA, Schlessinger J. Identification of a new Pyk2 target protein with Arf-GAP activity. Mol Cell Biol. 1999 Mar;19(3):2338-50. PMID:10022920
- ↑ Kruljac-Letunic A, Moelleken J, Kallin A, Wieland F, Blaukat A. The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. J Biol Chem. 2003 Aug 8;278(32):29560-70. Epub 2003 May 27. PMID:12771146 doi:10.1074/jbc.M302278200
- ↑ Takahashi T, Yamashita H, Nagano Y, Nakamura T, Ohmori H, Avraham H, Avraham S, Yasuda M, Matsumoto M. Identification and characterization of a novel Pyk2/related adhesion focal tyrosine kinase-associated protein that inhibits alpha-synuclein phosphorylation. J Biol Chem. 2003 Oct 24;278(43):42225-33. Epub 2003 Jul 31. PMID:12893833 doi:10.1074/jbc.M213217200
- ↑ Taniyama Y, Weber DS, Rocic P, Hilenski L, Akers ML, Park J, Hemmings BA, Alexander RW, Griendling KK. Pyk2- and Src-dependent tyrosine phosphorylation of PDK1 regulates focal adhesions. Mol Cell Biol. 2003 Nov;23(22):8019-29. PMID:14585963
- ↑ Dylla SJ, Deyle DR, Theunissen K, Padurean AM, Verfaillie CM. Integrin engagement-induced inhibition of human myelopoiesis is mediated by proline-rich tyrosine kinase 2 gene products. Exp Hematol. 2004 Apr;32(4):365-74. PMID:15050747 doi:10.1016/j.exphem.2004.01.001
- ↑ Park SY, Avraham HK, Avraham S. RAFTK/Pyk2 activation is mediated by trans-acting autophosphorylation in a Src-independent manner. J Biol Chem. 2004 Aug 6;279(32):33315-22. Epub 2004 May 27. PMID:15166227 doi:10.1074/jbc.M313527200
- ↑ Hjorthaug HS, Aasheim HC. Ephrin-A1 stimulates migration of CD8+CCR7+ T lymphocytes. Eur J Immunol. 2007 Aug;37(8):2326-36. PMID:17634955 doi:10.1002/eji.200737111
- ↑ Roberts WG, Ung E, Whalen P, Cooper B, Hulford C, Autry C, Richter D, Emerson E, Lin J, Kath J, Coleman K, Yao L, Martinez-Alsina L, Lorenzen M, Berliner M, Luzzio M, Patel N, Schmitt E, LaGreca S, Jani J, Wessel M, Marr E, Griffor M, Vajdos F. Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271. Cancer Res. 2008 Mar 15;68(6):1935-44. PMID:18339875 doi:68/6/1935
- ↑ Sun CK, Man K, Ng KT, Ho JW, Lim ZX, Cheng Q, Lo CM, Poon RT, Fan ST. Proline-rich tyrosine kinase 2 (Pyk2) promotes proliferation and invasiveness of hepatocellular carcinoma cells through c-Src/ERK activation. Carcinogenesis. 2008 Nov;29(11):2096-105. doi: 10.1093/carcin/bgn203. Epub 2008, Sep 1. PMID:18765415 doi:10.1093/carcin/bgn203
- ↑ Ruusala A, Aspenstrom P. The atypical Rho GTPase Wrch1 collaborates with the nonreceptor tyrosine kinases Pyk2 and Src in regulating cytoskeletal dynamics. Mol Cell Biol. 2008 Mar;28(5):1802-14. Epub 2007 Dec 17. PMID:18086875 doi:10.1128/MCB.00201-07
- ↑ Xu J, Gao XP, Ramchandran R, Zhao YY, Vogel SM, Malik AB. Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating beta2 integrins. Nat Immunol. 2008 Aug;9(8):880-6. doi: 10.1038/ni.1628. Epub 2008 Jun 29. PMID:18587400 doi:10.1038/ni.1628
- ↑ Gao C, Blystone SD. A Pyk2-Vav1 complex is recruited to beta3-adhesion sites to initiate Rho activation. Biochem J. 2009 Apr 28;420(1):49-56. doi: 10.1042/BJ20090037. PMID:19207108 doi:10.1042/BJ20090037
- ↑ Allen JG, Lee MR, Han CY, Scherrer J, Flynn S, Boucher C, Zhao H, O'Connor AB, Roveto P, Bauer D, Graceffa R, Richards WG, Babij P. Identification of small molecule inhibitors of proline-rich tyrosine kinase 2 (Pyk2) with osteogenic activity in osteoblast cells. Bioorg Med Chem Lett. 2009 Sep 1;19(17):4924-8. doi: 10.1016/j.bmcl.2009.07.084. , Epub 2009 Jul 22. PMID:19648005 doi:10.1016/j.bmcl.2009.07.084
- ↑ Rufanova VA, Alexanian A, Wakatsuki T, Lerner A, Sorokin A. Pyk2 mediates endothelin-1 signaling via p130Cas/BCAR3 cascade and regulates human glomerular mesangial cell adhesion and spreading. J Cell Physiol. 2009 Apr;219(1):45-56. doi: 10.1002/jcp.21649. PMID:19086031 doi:10.1002/jcp.21649
- ↑ Shen X, Xi G, Radhakrishnan Y, Clemmons DR. Recruitment of Pyk2 to SHPS-1 signaling complex is required for IGF-I-dependent mitogenic signaling in vascular smooth muscle cells. Cell Mol Life Sci. 2010 Nov;67(22):3893-903. doi: 10.1007/s00018-010-0411-x. Epub, 2010 Jun 3. PMID:20521079 doi:10.1007/s00018-010-0411-x
- ↑ Lim ST, Miller NL, Nam JO, Chen XL, Lim Y, Schlaepfer DD. Pyk2 inhibition of p53 as an adaptive and intrinsic mechanism facilitating cell proliferation and survival. J Biol Chem. 2010 Jan 15;285(3):1743-53. doi: 10.1074/jbc.M109.064212. Epub 2009 , Oct 30. PMID:19880522 doi:10.1074/jbc.M109.064212
- ↑ Collins M, Bartelt RR, Houtman JC. T cell receptor activation leads to two distinct phases of Pyk2 activation and actin cytoskeletal rearrangement in human T cells. Mol Immunol. 2010 May;47(9):1665-74. doi: 10.1016/j.molimm.2010.03.009. Epub 2010, Apr 9. PMID:20381867 doi:10.1016/j.molimm.2010.03.009
- ↑ Liebau MC, Hopker K, Muller RU, Schmedding I, Zank S, Schairer B, Fabretti F, Hohne M, Bartram MP, Dafinger C, Hackl M, Burst V, Habbig S, Zentgraf H, Blaukat A, Walz G, Benzing T, Schermer B. Nephrocystin-4 regulates Pyk2-induced tyrosine phosphorylation of nephrocystin-1 to control targeting to monocilia. J Biol Chem. 2011 Apr 22;286(16):14237-45. doi: 10.1074/jbc.M110.165464. Epub, 2011 Feb 28. PMID:21357692 doi:10.1074/jbc.M110.165464
- ↑ Sun CK, Ng KT, Lim ZX, Cheng Q, Lo CM, Poon RT, Man K, Wong N, Fan ST. Proline-rich tyrosine kinase 2 (Pyk2) promotes cell motility of hepatocellular carcinoma through induction of epithelial to mesenchymal transition. PLoS One. 2011 Apr 20;6(4):e18878. doi: 10.1371/journal.pone.0018878. PMID:21533080 doi:10.1371/journal.pone.0018878
- ↑ Lipinski CA, Loftus JC. Targeting Pyk2 for therapeutic intervention. Expert Opin Ther Targets. 2010 Jan;14(1):95-108. doi: 10.1517/14728220903473194. PMID:20001213 doi:10.1517/14728220903473194
- ↑ Walker DP, Zawistoski MP, McGlynn MA, Li JC, Kung DW, Bonnette PC, Baumann A, Buckbinder L, Houser JA, Boer J, Mistry A, Han S, Xing L, Guzman-Perez A. Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity. Bioorg Med Chem Lett. 2009 Jun 15;19(12):3253-8. Epub 2009 Apr 24. PMID:19428251 doi:10.1016/j.bmcl.2009.04.093
- ↑ Han S, Mistry A, Chang JS, Cunningham D, Griffor M, Bonnette PC, Wang H, Chrunyk BA, Aspnes GE, Walker DP, Brosius AD, Buckbinder L. Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique (DFG-out) conformation and enables inhibitor design. J Biol Chem. 2009 May 8;284(19):13193-201. Epub 2009 Feb 25. PMID:19244237 doi:10.1074/jbc.M809038200
- ↑ Vanarotti MS, Miller DJ, Guibao CD, Nourse A, Zheng JJ. Structural and mechanistic insights into the interaction between Pyk2 and Paxillin LD motifs. J Mol Biol. 2014 Aug 28. pii: S0022-2836(14)00457-4. doi:, 10.1016/j.jmb.2014.08.014. PMID:25174335 doi:http://dx.doi.org/10.1016/j.jmb.2014.08.014
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