Subcellular Redistribution of Focal Adhesion Kinase and Its Related Nonkinase in Hypertrophic Myocardium

Abstract

Abstract-Focal adhesion kinase (FAK) and focal adhesion kinase-related nonkinase (FRNK) are likely involved in mechanical signaling during hypertension. We investigated expression, subcellular distribution, and phosphorylation of FAK, as well as FRNK in left ventricles of spontaneously hypertensive heart failure rats. Key Words: hypertrophy Ⅲ heart failure Ⅲ kinase Ⅲ cell signaling O ur studies on lean female spontaneously hypertensive heart failure (SHHF) rats 1 have shown that myocyte cross-sectional growth responsible for ventricular wall thickening reaches a maximum at Ϸ4 months of age and remains stable thereafter. Myocyte lengthening, which underlies ventricular chamber dilatation, begins at 6 months of age and continues progressively with aging until the rats develop congestive heart failure (CHF) at 22 to 24 months of age. The switch from cross-sectional growth to myocyte lengthening Ϸ6 months in SHHF rats suggests that maladaptive remodeling and abnormal growth of cardiac myocytes begins long before overt cardiac decompensation. Therefore, the key to decipher the molecular mechanisms involved in the transition of concentric cardiac hypertrophy to maladaptive remodeling is to determine the signaling molecules that control series sarcomere assembly in cardiac myocytes.Focal adhesion kinase (FAK) is activated in cardiac myocytes and fibroblasts by in vitro treatment with a variety of hypertrophic stimuli. 2,3 The C-terminus of FAK is expressed as a separate protein known as focal adhesion kinase-related nonkinase (FRNK) in certain cell types. FRNK inhibits FAK tyrosine phosphorylation and endothelin-induced cardiac myocyte hypertrophy. 2 Recent studies have also shown that FAK is phosphorylated and activated during cardiac hypertrophy after acute pressure overload. 4 -6 The phosphorylation and activation of FAK appears to be transient and returns to normal levels after 1 week of overload. Thus, the potential role of FAK and FRNK in continuous remodeling of cardiac myocytes caused by chronic hypertension remains to be defined. FAK and FRNK may play a key role in cytoskeletal remodeling and maladaptive shape change of cardiac myocytes in SHHF rats.Serine phosphorylation of FAK and FRNK follows FAK tyrosine phosphorylation. 7 FAK become prominently phosphorylated on serine residues in a mitosis-specific fashion. 8 Serines 722 and 910 are 2 major serine phosphorylation sites of FAK in interphase cells. 7 The exact roles of these serine phosphorylation in mechanical signal transduction and cardiac hypertrophy remain to be investigated.In the present study, we examined expression and relationship between subcellular localization and phosphorylation of FAK and of FRNK in the left ventricles (LVs) of SHHF rats. Our results indicate that FAK is increased and translocated to membrane cytoskeleton, intercalated disks, and nuclei during cardiac hypertrophy in SHHF rats. The nuclear translocation of integrin-mediated signaling molecules may play an important role in regulating mechanical signal transduction to the nuc...

PIAS1-mediated Sumoylation of Focal Adhesion Kinase Activates Its Autophosphorylationn

“…However, the presence of truncated forms of FAK and of the full-length protein in the nucleus has already been reported, suggesting that FAK may have a role in the nucleus under some circumstances (55,56). An attractive hypothesis would thus be that FAK undergoes a nucleocytoplasmic cycling that allows its nuclear sumoylation in the presence of PIAS1.…”

Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions

“…Additional studies revealed that full-length FAK and Pyk2 could localize to the nucleus under appropriate conditions and in a number of different cell types (Aoto et al, 2002;Yi et al, 2003). Recent evidence has shed some light on the mechanisms regulating nuclear localization and nuclear function.…”

“…1). However, both full-length FAK and the C-terminal domain of FAK can be localized to the nucleus in cardiomyocytes (Yi et al, 2003). This implies an alternative mechanism because the C-terminal domain lacks the N-terminal nuclear localization sequences, but a potential mechanism has not been defined.…”

Cardiac-specific haploinsufficiency of β-catenin attenuates cardiac hypertrophy but enhances fetal gene expression in response to aortic constriction

“…LV tissues from 5 mice in each group were homogenized using a PT1200C Polytron Homogenizer in ice-cold Tris/Triton extraction buffer (10mM Tris-HCl, 50mM NaCl, 5mM EGTA, 1%Triton X-100, pH 7.4) with phosphatase inhibitors (0.1mM Na 3 VO 4 , 30mM Na 4 P 2 O 7 , 50mM NaF) and proteinase inhibitors (10mg/ml PMSF, 1μg/ml aprotinin) [16]. The homogenates were centrifuged at 15,000 g for 15 minutes and separated into Triton soluble supernatant and insoluble pellet.…”