A Novel Role for FAK as a Protease-Targeting Adaptor Protein

Abstract

Cell migration on extracellular matrix requires the turnover of integrin-dependent adhesions. The nonreceptor tyrosine kinases Src and FAK regulate focal-adhesion turnover by poorly understood mechanisms. ERK/MAP kinase-mediated activation of the protease Calpain 2 also promotes focal-adhesion turnover; however, it is not known if this is linked to the activities of Src and FAK. Calpain 2 has previously been demonstrated to colocalize with focal-adhesion structures and can cleave several focal-adhesion complex components, including FAK. Studies utilizing Calpain inhibitors or Calpain-deficient cells confirm that Calpain's role in regulating focal-adhesion turnover is necessary for cell migration. We have identified a novel and kinase-independent function for FAK as an adaptor molecule that mediates the assembly of a complex consisting of at least Calpain 2 and p42ERK. Mutation of proline residues (Pro2) in the amino-terminal region of FAK blocks direct binding with Calpain 2 and also prevents formation of the Calpain 2/p42ERK complex in cells. We show that both complex formation and MEK/ERK activity are associated with Calpain-mediated proteolysis of FAK and focal adhesion turnover during transformation and migration. Furthermore, FAK is necessary for recruiting both Calpain 2 and p42ERK/MAPK to peripheral adhesion sites facilitating maximal Calpain activity.

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

“…FAK is also a target for calpain proteolysis in v-src transformed cells [197]. The relationship between FAK and calpain is complex: FAK is required to recruit calpain to focal adhesions and for calpain activation, and is subsequently a target for proteolysis during focal adhesion turnover [197].…”

“…The relationship between FAK and calpain is complex: FAK is required to recruit calpain to focal adhesions and for calpain activation, and is subsequently a target for proteolysis during focal adhesion turnover [197]. Expression of FAK deficient for calpain binding prevents focal adhesion turnover.…”

“…Expression of FAK deficient for calpain binding prevents focal adhesion turnover. Indeed, FAK can serve as an adapter to assemble calpain together with its activator ERK, and this assembly is necessary for calpain proteolysis of FAK [197]. While proteolysis of FAK at first glance appear at odds with FAK's role in stimulating adhesion turnover [79,86,198], proteolysis probably occurs subsequent to, or in parallel with, activation of effectors executing adhesion turnover.…”

Signal Transduction and Actin in the Regulation of G1-Phase Progression

“…128 In addition, it was demonstrated that FAK induces the formation of a complex constituting calpain 2, FAK, and ERK. 129 These data suggest that FAK is critical to the integration of migratory signals from growth factor receptors and integrins through the ERK pathway to the calpain proteolytic system, resulting in focal adhesion turnover and cell migration. 130 Actin microfilaments have also been demonstrated to regulate integrins.…”

A tumour suppressor function of caspase-8?

“…10 Caspase-8 promotes mobility, at least in part, by calpain activation, and calpains are known to be involved in the regulation of the adhesion complex. 11 Calpains have also been implicated in accurate chromosomal alignment at metaphase 12 and there is some evidence that caspase-8-deficient MEFs are more prone to become multinucleated. 10 It is rather a large leap to argue from here that caspase-8 deficiency contributes to the chromosomal instability that is a hallmark of many tumours (and which may be implicated in transformation), 13 but the ability of viral FLIP to induce transformation, 14 and the elevated levels of cFLIP in some human cancers, 15 might be due to inhibition of caspase-8-mediated calpain activation instead of inhibition of caspase-8-mediated apoptosis.…”