| Structural highlights
Function
[MEF2C_MOUSE] Transcription activator which binds specifically to the MEF2 element present in the regulatory regions of many muscle-specific genes. Controls cardiac morphogenesis and myogenesis, and is also involved in vascular development. May also be involved in neurogenesis and in the development of cortical architecture. Isoform 3 and isoform 4, which lack the repressor domain, are more active than isoform 1, isoform 2 and isoform 5 (By similarity). Plays an essential role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. Crucial for normal neuronal development, distribution, and electrical activity in the neocortex. Necessary for proper development of megakaryocytes and platelets and for bone marrow B-lymphopoiesis. Required for B-cell survival and proliferation in response to BCR stimulation, efficient IgG1 antibody responses to T-cell-dependent antigens and for normal induction of germinal center B-cells.[UniProtKB:Q06413][1] [2] [3] [4] [5] [6] [7] [FAK1_MOUSE] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development and placenta development. Required for embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), EPHA2, netrin receptors and LDL receptors. 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 the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 9 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription (By similarity).[8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
Publication Abstract from PubMed
Focal adhesion kinase (FAK) has emerged as a mediator of mechanotransduction in cardiomyocytes, regulating gene expression during hypertrophic remodeling. However, how FAK signaling is relayed onward to the nucleus is unclear. Here, we show that FAK interacts with and regulates myocyte enhancer factor 2 (MEF2), a master cardiac transcriptional regulator. In cardiomyocytes exposed to biomechanical stimulation, FAK accumulates in the nucleus, binds to and upregulates the transcriptional activity of MEF2 through an interaction with the FAK focal adhesion targeting (FAT) domain. In the crystal structure (2.9 A resolution), FAT binds to a stably folded groove in the MEF2 dimer, known to interact with regulatory cofactors. FAK cooperates with MEF2 to enhance the expression of Jun in cardiomyocytes, an important component of hypertrophic response to mechanical stress. These findings underscore a connection between the mechanotransduction involving FAK and transcriptional regulation by MEF2, with potential relevance to the pathogenesis of cardiac disease.
FAK Forms a Complex with MEF2 to Couple Biomechanical Signaling to Transcription in Cardiomyocytes.,Cardoso AC, Pereira AHM, Ambrosio ALB, Consonni SR, Rocha de Oliveira R, Bajgelman MC, Dias SMG, Franchini KG Structure. 2016 Aug 2;24(8):1301-1310. doi: 10.1016/j.str.2016.06.003. Epub 2016 , Jul 14. PMID:27427476[25]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Angelelli C, Magli A, Ferrari D, Ganassi M, Matafora V, Parise F, Razzini G, Bachi A, Ferrari S, Molinari S. Differentiation-dependent lysine 4 acetylation enhances MEF2C binding to DNA in skeletal muscle cells. Nucleic Acids Res. 2008 Feb;36(3):915-28. Epub 2007 Dec 17. PMID:18086704 doi:http://dx.doi.org/gkm1114
- ↑ Wilker PR, Kohyama M, Sandau MM, Albring JC, Nakagawa O, Schwarz JJ, Murphy KM. Transcription factor Mef2c is required for B cell proliferation and survival after antigen receptor stimulation. Nat Immunol. 2008 Jun;9(6):603-12. doi: 10.1038/ni.1609. Epub 2008 Apr 27. PMID:18438409 doi:http://dx.doi.org/10.1038/ni.1609
- ↑ Li H, Radford JC, Ragusa MJ, Shea KL, McKercher SR, Zaremba JD, Soussou W, Nie Z, Kang YJ, Nakanishi N, Okamoto S, Roberts AJ, Schwarz JJ, Lipton SA. Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9397-402. doi:, 10.1073/pnas.0802876105. Epub 2008 Jul 1. PMID:18599437 doi:http://dx.doi.org/10.1073/pnas.0802876105
- ↑ Barbosa AC, Kim MS, Ertunc M, Adachi M, Nelson ED, McAnally J, Richardson JA, Kavalali ET, Monteggia LM, Bassel-Duby R, Olson EN. MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function. Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9391-6. doi:, 10.1073/pnas.0802679105. Epub 2008 Jul 1. PMID:18599438 doi:http://dx.doi.org/10.1073/pnas.0802679105
- ↑ Gekas C, Rhodes KE, Gereige LM, Helgadottir H, Ferrari R, Kurdistani SK, Montecino-Rodriguez E, Bassel-Duby R, Olson E, Krivtsov AV, Armstrong S, Orkin SH, Pellegrini M, Mikkola HK. Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis. Blood. 2009 Apr 9;113(15):3461-71. doi: 10.1182/blood-2008-07-167577. Epub 2009, Feb 11. PMID:19211936 doi:http://dx.doi.org/10.1182/blood-2008-07-167577
- ↑ Lin Q, Schwarz J, Bucana C, Olson EN. Control of mouse cardiac morphogenesis and myogenesis by transcription factor MEF2C. Science. 1997 May 30;276(5317):1404-7. PMID:9162005
- ↑ Lin Q, Lu J, Yanagisawa H, Webb R, Lyons GE, Richardson JA, Olson EN. Requirement of the MADS-box transcription factor MEF2C for vascular development. Development. 1998 Nov;125(22):4565-74. PMID:9778514
- ↑ Schlaepfer DD, Hanks SK, Hunter T, van der Geer P. Integrin-mediated signal transduction linked to Ras pathway by GRB2 binding to focal adhesion kinase. Nature. 1994 Dec 22-29;372(6508):786-91. PMID:7997267
- ↑ Furuta Y, Ilic D, Kanazawa S, Takeda N, Yamamoto T, Aizawa S. Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK. Oncogene. 1995 Nov 16;11(10):1989-95. PMID:7478517
- ↑ Schlaepfer DD, Hunter T. Focal adhesion kinase overexpression enhances ras-dependent integrin signaling to ERK2/mitogen-activated protein kinase through interactions with and activation of c-Src. J Biol Chem. 1997 May 16;272(20):13189-95. PMID:9148935
- ↑ Owen JD, Ruest PJ, Fry DW, Hanks SK. Induced focal adhesion kinase (FAK) expression in FAK-null cells enhances cell spreading and migration requiring both auto- and activation loop phosphorylation sites and inhibits adhesion-dependent tyrosine phosphorylation of Pyk2. Mol Cell Biol. 1999 Jul;19(7):4806-18. PMID:10373530
- ↑ Sieg DJ, Hauck CR, Ilic D, Klingbeil CK, Schaefer E, Damsky CH, Schlaepfer DD. FAK integrates growth-factor and integrin signals to promote cell migration. Nat Cell Biol. 2000 May;2(5):249-56. PMID:10806474 doi:http://dx.doi.org/10.1038/35010517
- ↑ Xie B, Zhao J, Kitagawa M, Durbin J, Madri JA, Guan JL, Fu XY. Focal adhesion kinase activates Stat1 in integrin-mediated cell migration and adhesion. J Biol Chem. 2001 Jun 1;276(22):19512-23. Epub 2001 Feb 21. PMID:11278462 doi:http://dx.doi.org/10.1074/jbc.M009063200
- ↑ Izaguirre G, Aguirre L, Hu YP, Lee HY, Schlaepfer DD, Aneskievich BJ, Haimovich B. The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase. J Biol Chem. 2001 Aug 3;276(31):28676-85. Epub 2001 May 21. PMID:11369769 doi:http://dx.doi.org/10.1074/jbc.M101678200
- ↑ Xie Z, Sanada K, Samuels BA, Shih H, Tsai LH. Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration. Cell. 2003 Aug 22;114(4):469-82. PMID:12941275
- ↑ Zhai J, Lin H, Nie Z, Wu J, Canete-Soler R, Schlaepfer WW, Schlaepfer DD. Direct interaction of focal adhesion kinase with p190RhoGEF. J Biol Chem. 2003 Jul 4;278(27):24865-73. Epub 2003 Apr 17. PMID:12702722 doi:http://dx.doi.org/10.1074/jbc.M302381200
- ↑ Shen TL, Park AY, Alcaraz A, Peng X, Jang I, Koni P, Flavell RA, Gu H, Guan JL. Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J Cell Biol. 2005 Jun 20;169(6):941-52. PMID:15967814 doi:http://dx.doi.org/10.1083/jcb.200411155
- ↑ Brown MC, Cary LA, Jamieson JS, Cooper JA, Turner CE. Src and FAK kinases cooperate to phosphorylate paxillin kinase linker, stimulate its focal adhesion localization, and regulate cell spreading and protrusiveness. Mol Biol Cell. 2005 Sep;16(9):4316-28. Epub 2005 Jul 6. PMID:16000375 doi:http://dx.doi.org/10.1091/mbc.E05-02-0131
- ↑ Braren R, Hu H, Kim YH, Beggs HE, Reichardt LF, Wang R. Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation. J Cell Biol. 2006 Jan 2;172(1):151-62. PMID:16391003 doi:http://dx.doi.org/10.1083/jcb.200506184
- ↑ Chang F, Lemmon CA, Park D, Romer LH. FAK potentiates Rac1 activation and localization to matrix adhesion sites: a role for betaPIX. Mol Biol Cell. 2007 Jan;18(1):253-64. Epub 2006 Nov 8. PMID:17093062 doi:http://dx.doi.org/10.1091/mbc.E06-03-0207
- ↑ Lim ST, Chen XL, Lim Y, Hanson DA, Vo TT, Howerton K, Larocque N, Fisher SJ, Schlaepfer DD, Ilic D. Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation. Mol Cell. 2008 Jan 18;29(1):9-22. doi: 10.1016/j.molcel.2007.11.031. PMID:18206965 doi:10.1016/j.molcel.2007.11.031
- ↑ Chu PY, Huang LY, Hsu CH, Liang CC, Guan JL, Hung TH, Shen TL. Tyrosine phosphorylation of growth factor receptor-bound protein-7 by focal adhesion kinase in the regulation of cell migration, proliferation, and tumorigenesis. J Biol Chem. 2009 Jul 24;284(30):20215-26. doi: 10.1074/jbc.M109.018259. Epub, 2009 May 27. PMID:19473962 doi:http://dx.doi.org/10.1074/jbc.M109.018259
- ↑ Pylayeva Y, Gillen KM, Gerald W, Beggs HE, Reichardt LF, Giancotti FG. Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Invest. 2009 Feb;119(2):252-66. doi: 10.1172/JCI37160. Epub 2009 Jan 19. PMID:19147981 doi:10.1172/JCI37160
- ↑ Clemente CF, Xavier-Neto J, Dalla Costa AP, Consonni SR, Antunes JE, Rocco SA, Pereira MB, Judice CC, Strauss B, Joazeiro PP, Matos-Souza JR, Franchini KG. Focal adhesion kinase governs cardiac concentric hypertrophic growth by activating the AKT and mTOR pathways. J Mol Cell Cardiol. 2012 Feb;52(2):493-501. doi: 10.1016/j.yjmcc.2011.10.015., Epub 2011 Oct 26. PMID:22056317 doi:http://dx.doi.org/10.1016/j.yjmcc.2011.10.015
- ↑ Cardoso AC, Pereira AHM, Ambrosio ALB, Consonni SR, Rocha de Oliveira R, Bajgelman MC, Dias SMG, Franchini KG. FAK Forms a Complex with MEF2 to Couple Biomechanical Signaling to Transcription in Cardiomyocytes. Structure. 2016 Aug 2;24(8):1301-1310. doi: 10.1016/j.str.2016.06.003. Epub 2016 , Jul 14. PMID:27427476 doi:http://dx.doi.org/10.1016/j.str.2016.06.003
|
