PINCH1 regulates Akt1 activation and enhances radioresistance by inhibiting PP1α

Abstract

Tumor cell resistance to ionizing radiation and chemotherapy is a major obstacle in cancer therapy. One factor contributing to this is integrin-mediated adhesion to ECM. The adapter protein particularly interesting new cysteine-histidine-rich 1 (PINCH1) is recruited to integrin adhesion sites and promotes cell survival, but the mechanisms underlying this effect are not well understood. Here we have shown that PINCH1 is expressed at elevated levels in human tumors of diverse origins relative to normal tissue. Furthermore, PINCH1 promoted cell survival upon treatment with ionizing radiation in vitro and in vivo by perpetuating Akt1 phosphorylation and activity. Mechanistically, PINCH1 was found to directly bind to protein phosphatase 1α (PP1α) -an Akt1-regulating protein -and inhibit PP1α activity, resulting in increased Akt1 phosphorylation and enhanced radioresistance. Thus, our data suggest that targeting signaling molecules such as PINCH1 that function downstream of focal adhesions (the complexes that mediate tumor cell adhesion to ECM) may overcome radio-and chemoresistance, providing new therapeutic approaches for cancer.

PINCH-1 promotes Bcl-2-dependent survival signalling and inhibits JNK-mediated apoptosis in the primitive endoderm.

“…It has been reported that PINCH-1 protects tumour cells from Bax-dependent apoptosis through phosphorylation and activation of ERK1/2 and AKT or by downregulating expression and phosphorylation of the pro-apoptotic protein Bim (Chen et al, 2008;Eke et al, 2010). To test whether this is also occurring in PrE cells, we determined the phosphorylation levels of ERK1/2 and AKT in WT and PINCH-1 2/2 PrE cells cultured for 24 or 48 hours on FN.…”

“…PINCH-1 can bind several actin modulating proteins (Legate et al, 2006;Wickström et al, 2010), the Ras suppressor protein 1 (RSU-1) and the protein phosphatase 1a (PP1a). The latter two interactions were shown to modulate MAPK and phosphoinositol 3-kinase (PI3K)/AKT signalling, respectively (Masuelli and Cutler, 1996;Dougherty et al, 2008;Eke et al, 2010).…”

“…Similarly, embryonic stem (ES)-cell-derived embryoid bodies (EBs), which mimic peri-implantation development (Coucouvanis and Martin, 1995;Montanez et al, 2007) identified PINCH-1 as an important survival factor for PrE cells . PINCH-1 was also shown to protect tumour cells from apoptosis by enhancing the activities of the prosurvival proteins ERK1/2 and AKT (Chen et al, 2008;Eke et al, 2010;Sandfort et al, 2010). How PINCH-1 regulates survival of the PrE is not known.…”

Integrin-linked kinase at a glance

“…An alternative possibility is that ILK and ILKinteracting protein(s) regulate oncogenic kinases by controlling the activity of phosphatases. This has been shown for Pinch-1, which binds to and inhibits protein phosphatase 1a (PP1a) resulting in sustained PKB phosphorylation and activity (Eke et al, 2010). Consequently, reducing the amounts of the IPP complex in FAs will concomitantly result in an increased PP1a activity and decreased PKB function.…”

A firm grip does not always pay off: a new Phact(r) 4 integrin signaling

“…Many potential PP1 regulatory partners have been found. Besides tensin (Eto et al 2007), PINCH1 has recently been identified as a regulator of PP1a in FAs (Eke et al 2010). PINCH is a constitutive component of the integrin-linked kinase, PINCH, and parvin (IPP) complex (Legate et al 2006).…”