Heterogeneous nuclear ribonucleoprotein A2 is a SET-binding protein and a PP2A inhibitor

Abstract

The oncoprotein SET participates in a diversity of cellular functions including cell proliferation. Its role on cell cycle progression is likely mediated by inhibiting cyclin B-cdk1 and the protein phosphatase 2A (PP2A). On identifying new SET cellular partners, we found that SET interacts in vitro and in vivo with the heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2); a protein involved in various aspects of mRNA biogenesis. The SET-binding region of hnRNPA2 is the RNP1 sequence that belongs to the RNA-binding domain (RBD) of this protein. We also found that hnRNPA2 has much higher affinity for singlestanded DNA than for SET. On analysing the effect of hnRNPA2 on PP2A inhibition by SET, we observed that hnRNPA2 cooperates with SET on PP2A inhibition. This is because we found that hnRNPA2 is also a PP2A inhibitor. HnRNPA2 interacts with PP2A by the RNP1 sequence; however, to inhibit PP2A activity, the complete RBD is needed. We also observed that overexpression of hnRNPA2 inhibits PP2A activity and stimulates cell proliferation. Interestingly, the overexpression of the complete RBD is sufficient to stimulate proliferation. As hnRNPA2 is overexpressed in a variety of human tumors, our results suggest that hnRNPA2 might participate in oncogenesis by stimulating cell proliferation.

TSPY and its X-encoded homologue interact with cyclin B but exert contrasting functions on cyclin-dependent kinase 1 activities

“…Significantly, all TSPY isoforms harbor the entire or part of a conserved domain of B160 amino acids, termed SET/NAP domain initially identified in the human SET oncoprotein and nucleosome assembly protein-1 (NAP-1) (Tsuchiya et al, 1995;Vogel et al, 1998). The SET/NAP proteins are structurally related and serve a wide range of biological functions, including cell-cycle regulation, histone chaperone, chromatin organization, transcription modulation and steroid receptor co-regulation (Adachi et al, 1994;Kellogg et al, 1995;Estanyol et al, 1999;Compagnone et al, 2000;Chai et al, 2001;Seo et al, 2001;Canela et al, 2003;Ozbun et al, 2003;Gamble et al, 2005;Kandilci and Grosveld, 2005;Vera et al, 2005;Kido and Lau, 2006). Currently, it is uncertain if these TSPY isoforms possess the same or different functions, retention of the SET/NAP domain suggests that this conserved domain could be important for their biological action(s).…”

Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells

“…Furthermore, although a role in proliferation of human cell lines was previously described, 61 and overexpression of HNRNPA2B1 has been found in PDAC cell lines 62 a direct role of HNRNPA2B1 in tumorogenesis was not proved until recently. Golan-Gerst and coworkers 47 showed, on the one hand, that NIH 3T3 overexpressing HNRNPA2B1 became transformed, formed colonies in soft agar and were tumorigenic in nude mice, and, on the other hand, that knock-down of HNRNPA2B1 in glioblastoma cells inhibited tumor formation.…”

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

“…Moreover, the PP2A subunit PR65/A, which is also overexpressed in BCR/ABL þ cells, may also contribute to PP2A inactivation, as PR65/A overexpression could sequester the catalytic or variable subunits or act as a PP2Ac inhibitor (Kamibayashi et al, 1992;Wera et al, 1995). Interestingly, it was recently reported that hnRNP A2, an hnRNP with high sequence, structure and function similarity with hnRNP A1, inhibits PP2A activity upon interaction with SET (Vera et al, 2006). Because also hnRNP A2 expression is induced by BCR/ABL (our unpublished observation), the hnRNP A2/SET-dependent inhibition of PP2A may represent another mechanism whereby BCR/ABL induces the loss of PP2A function in CML-BC.…”