Hematopoietic PBX-interacting protein (HPIP) is over expressed in breast infiltrative ductal carcinoma and regulates cell adhesion and migration through modulation of focal adhesion dynamics

S. Bugide, D. David, A. Nair, Nagarajan Kannan, V. S.K. Samanthapudi, J. Prabhakar, B. Manavathi

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The scaffolding protein, hematopoietic PBX-interacting protein (HPIP/PBXIP1), regulates cell migration necessary for cancer cell dissemination. However, the mechanism that governs this process remains unknown. We show here that HPIP expression is associated with stages of breast cancer where cell dissemination results in poor patient outcome. Our investigation finds a novel association of HPIP with focal adhesion kinase (FAK) regulating FA dynamics. Interestingly, this interaction that led to activation of FAK protein was mediated by the C-terminal domain of HPIP and not the typical integrin-binding motif. Further, short hairpin RNA-mediated knockdown of FAK expression significantly reduced HPIP-induced cell migration indicating participation of FAK pathway. Live-cell time-lapse imaging and biochemical analysis further established the role of HPIP in microtubule-induced FA disassembly. We also found that HPIP-mediated MAPK activation led to phosphorylation and subsequent activation of calpain2, and the activated calpain2 in turn proteolyses FA protein, talin. Interestingly, HPIP is also proteolysed by calpain2 in breast cancer cells. The proteolysis of HPIP and talin by calpain2, and the activation of calapin2 by HPIP-mediated MAPK phosphorylation, is a novel regulatory axis to modulate the cell migration signal. Together, we have determined HPIP as a novel activator of FAK and a new substrate of calpain2. These molecular interactions between HPIP and FAK, and HPIP and calpain2 regulate cell adhesion and migration through modulation of FA dynamics.

Original languageEnglish (US)
Pages (from-to)4601-4612
Number of pages12
JournalOncogene
Volume34
Issue number35
DOIs
StatePublished - Aug 27 2015
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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