Phosphorylation of the N-terminal domain of p48 Ebp1 by CDK2 is required for tumorigenic function of p48

The long isoform of ErbB3 binding protein 1 (Ebp1), p48, strongly promotes tumorigenesis of glioblastoma, accelerating cell proliferation and transformation, while the short isoform, p42, which lacks the N-terminal 54 amino acids, inhibits tumor growth. However, it is unclear if the N-terminal domain of p48 regulates the oncogenic function of p48. Here, we show that p48, but not p42, interacts with cyclin-dependent kinase 2 (CDK2) through its N-terminal domain, resulting in the specific phosphorylation of serine 34 of p48. Overexpression of wild-type p48 greatly enhanced tumor cell growth, whereas phospho-ablated mutant S34A of p48, which is mutated at the CDK2 phosphorylation site, antagonizes cell proliferation and transformation. Moreover, phospho-ablated mutant S34A abrogated the ability of p48 to accelerate tumor cell growth in a mouse engraft model. Thus, our findings indicate that p48Ebp1 acts as an oncoprotein through selective interaction and/or modification of the N-terminal domain that does not exist in its short isoform p42.