Transient expression of FRNK reveals stage-specific requirement for focal adhesion kinase activity in cardiac growth.
Focal adhesion kinase (FAK) is strongly activated by integrins and growth factors and is essential for embryonic development. We previously showed that the C terminus of FAK is expressed as a separate protein termed FAK-related nonkinase (FRNK) in a smooth muscle cell-selective fashion and that FRNK functions to buffer FAK-dependent signals. We now show that FRNK is also transiently expressed in the neonatal myocardium, with peak levels occurring 5 to 7 days postnatal, just before cell cycle withdrawal. Using novel mouse models, we demonstrate that cardiac-selective expression of FRNK (leading to inhibition of FAK) starting at embryonic day 10.5 leads to a severe ventricular noncompaction defect associated with reduced cardiomyocyte proliferation. Remarkably, postnatal expression of nearly identical levels of FRNK is well tolerated and does not affect viability or anabolic cardiac growth. Nonetheless, FRNK expression in the adult heart does attenuate pathological cardiac hypertrophy following aortic banding, confirming and extending our previous data that this compensatory response is blunted in FAK null hearts. Our mechanistic studies in cultured neonatal cardiomyocytes reveal that FRNK expression induces p38/p27(kip)-dependent cell cycle withdrawal and attenuates extracellular signal-regulated kinase-dependent hypertrophic growth. These findings indicate that dynamic expression of FRNK in the neonatal heart may function to promote cardiomyocyte quiescence in an environment that is particularly rich in growth factors and growth promoting extracellular matrices.
DiMichele
Laura A
LA
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Hakim
Zeenat S
ZS
Sayers
Rebecca L
RL
Rojas
Mauricio
M
Schwartz
Robert J
RJ
Mack
Christopher P
CP
Taylor
Joan M
JM
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006321:Heart / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D050760:Cyclin-Dependent Kinase Inhibitor p27; C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases