Recent genetic evidence indicates that the integrin class of fibronectin-binding adhesion receptors (5E1 and others) can regulate both the form and function of the heart. Integrin ligation drives recruitment of a number of structural and signaling molecules to the ventral plasma membrane collectively termed a """"""""focal adhesion"""""""" which serves to link the force-generating actin cytoskeleton inside the cell to the extracellular matrix (ECM), and to coordinate activation of downstream signaling pathways. The non-receptor tyrosine kinase, Focal Adhesion Kinase (FAK) is strongly activated by both integrins and growth factors, and is a likely candidate to integrate downstream signals from these diverse pathways during growth and development. Indeed, germline deletion of FAK results in mesodermal defects and embryonic lethality between E7.5-10 similar to the phenotype observed in both fibronectin-, and D5-null mice. Although a direct role for FAK in cardiac development has yet to be examined, hearts from FAK-null embryos revealed a lack of separate mesocardial and endocardial layers, indicative of a defect in cardiomyocyte maturation. Interestingly, recent work by our group and others clearly indicate that FAK is activated in cultured cardiomyocytes by a variety of hypertrophic stimuli including, phenylephrine (PE), endothelin I (ET-1), angiotensin II (AII), and hypo-osmotic stress, and that increased cardiac FAK activity is observed in vivo in hypertrophic hearts. The idea that FAK activation plays a direct role in the development of cardiomyocyte hypertrophy is evident from our seminal findings that the activation of FAK is required for PE-stimulated hypertrophy of cultured cells and similar findings from others that FAK is required for maximal ET-1 and stretch-induced hypertrophy in vitro. The experimental goals of this proposal are to test the hypothesis that FAK regulates cardiac development and pathological hypertrophy in vivo and to identify the FAK-dependent signaling pathways involved in these processes. We will generate genetically modified mice in which FAK will be deleted in a temporal and cardiac-restricted fashion using Cre/LoxP technology to examine a functional role for FAK in cardiac growth. We will also establish a cardiac cell culture model to identify FAK-dependent signals and target genes that are differentially regulated by hypertrophic stimuli. ? ? ?
| Cheng, Zhaokang; Zhu, Qiang; Dee, Rachel et al. (2017) Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth. J Biol Chem 292:2065-2079 |
| Giudice, Jimena; Taylor, Joan M (2017) Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34:49-55 |
| Cheng, Zhaokang; DiMichele, Laura A; Rojas, Mauricio et al. (2014) Focal adhesion kinase antagonizes doxorubicin cardiotoxicity via p21(Cip1.). J Mol Cell Cardiol 67:1-11 |
| Lenhart, Kaitlin C; Becherer, Abby L; Li, Jianbin et al. (2014) GRAF1 promotes ferlin-dependent myoblast fusion. Dev Biol 393:298-311 |
| Bai, Xue; Lenhart, Kaitlin C; Bird, Kim E et al. (2013) The smooth muscle-selective RhoGAP GRAF3 is a critical regulator of vascular tone and hypertension. Nat Commun 4:2910 |
| O'Neill 4th, Thomas J; Mack, Christopher P; Taylor, Joan M (2012) Germline deletion of FAK-related non-kinase delays post-natal cardiomyocyte mitotic arrest. J Mol Cell Cardiol 53:156-64 |
| Zajac, Britni; Hakim, Zeenat S; Cameron, Morgan V et al. (2012) Quantification of myocyte chemotaxis: a role for FAK in regulating directional motility. Methods Mol Biol 843:111-23 |
| Tandon, Panna; Conlon, Frank L; Taylor, Joan M (2012) ROCKs cause SHP-wrecks and broken hearts. Small GTPases 3:209-12 |
| Medlin, Matt D; Taylor, Joan M; Mack, Christopher P (2012) Quantifying sphingosine-1-phosphate-dependent activation of the RhoGTPases. Methods Mol Biol 874:89-97 |
| Cheng, Zhaokang; DiMichele, Laura A; Hakim, Zeenat S et al. (2012) Targeted focal adhesion kinase activation in cardiomyocytes protects the heart from ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol 32:924-33 |
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