Abstract
Protein Phosphatase type 2A (PP2A) represents a family of holoenzyme complexes with diverse biological activities. Specific holoenzyme complexes are thought to be deregulated during oncogenic transformation and oncogene-induced signaling. Since most studies on the role of this phosphatase family have relied on the use of generic PP2A inhibitors, the contribution of individual PP2A holoenzyme complexes in PP2A-controlled signaling pathways is largely unclear. To gain insight into this, we have constructed a set of shRNA vectors targeting the individual PP2A regulatory subunits for suppression by RNA interference. Here, we identify PR55γ and PR55δ as inhibitors of c-Jun NH2-terminal kinase (JNK) activation by UV irradiation. We show that PR55γ binds c-SRC and modulates the phosphorylation of serine 12 of c-SRC, a residue we demonstrate to be required for JNK activation by c-SRC. We also find that the physical interaction between PR55γ and c-SRC is sensitive to UV irradiation. Our data reveal a novel mechanism of c-SRC regulation whereby in response to stress c-SRC activity is regulated, at least in part, through loss of the interaction with its inhibitor, PR55γ.
Highlights
The Src family of nonreceptor tyrosine kinases are integral players in the mediation of various physiological processes such as cell motility, adhesion, proliferation, and survival [1]
We show that PR55c influences Jun NH2-terminal kinase (JNK) activity by inhibiting one of its upstream regulators, the proto-oncogene c-SRC, through dephosphorylation at one of the key residues on c-SRC, a site we show to be critical for c-SRC activation following cell stress
Overall our work describes the novel function of a specific Phosphatase type 2A (PP2A) subunit involved in cell survival and identifies a novel mechanism of c-SRC regulation
Summary
The Src family of nonreceptor tyrosine kinases are integral players in the mediation of various physiological processes such as cell motility, adhesion, proliferation, and survival [1]. C-SRC activation is negatively regulated by Carboxy Src Kinase (CSK) or its homologue CHK through Tyrosine 527 (Tyr527) phosphorylation [2]. This inhibitory phosphorylation promotes the assembly of the SH2, SH3, and kinase domains into a closed conformation [2]. C-SRC is activated by the binding of tyrosine-phosphorylated proteins to the SH2 domain, resulting in destabilization of the intermolecular interaction between Tyr527 and the SH2 domain [2]. C-SRC is autophosphorylated at Tyrosine 416 (Tyr416), a site within a segment of the kinase domain termed the activation loop, promoting a conformational change that allows the kinase to adopt an open active confirmation [2]
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