Protein tyrosine phosphatase PTPH1 potentiates receptor tyrosine kinase HER2 oncogenesis via a PDZ-coupled and phosphorylation-driven scaffold.

Abstract

Cancer cell overexpresses numerus proteins, however, how these up-regulated proteins, especially those enzymatically opposite kinases and phosphatases, act together to promote oncogenesis is unknown. Here, we reported that protein tyrosine phosphatase H1 (PTPH1) is a scaffold protein for receptor tyrosine kinase (HER2) to potentiate breast tumorigenesis. PTPH1 utilizes its PDZ domain to bind HER2, p38γ, PBK, and YAP1 and to increase HER2 nuclear translocation, stemness, and oncogenesis. PTPH1 de-phosphorylates HER2 and reciprocally increases HER2 protein expression dependent on cellular content. PTPH1 itself can be phosphorylated at S459 by redundant kinases p38γ and/or PBK, thereby distinctively regulating expression and/or turnover of scaffold proteins. Moreover, PTPH1 and HER2 cooperate to increase PBK and Yap1 transcription thus acting as an additional mechanism to activate the scaffold. PTPH1 protein levels are higher in HER2⁺ breast cancer in which their phosphorylated forms are inversely correlated, indicating an integrated oncogenic activity through coordinated PTPH1 phosphorylation and HER2 de-phosphorylation. Combinational, but not individual, application of scaffold-kinases' inhibitors suppresses xenograft growth in mice. Thus, a PDZ-coupled and phosphorylation-driven scaffold can integrate proliferative signaling of enzymatically distinct proteins as a super-oncogene and as a target for combination therapy.