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

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.

The interplay between HPIP and casein kinase 1α promotes renal cell carcinoma growth and metastasis via activation of mTOR pathway

“…Recently, accumulating evidence has revealed that HPIP functions as a promoter of the development and progression of cancers, including breast cancer, 2, 3 astrocytoma, 4 liver cancer, 5, 6 oral cell carcinoma, 7 colorectal cancer 8 and so on. However, the role of HPIP in RCC remains unclear.…”

Hematopoietic pre‐B cell leukemia transcription factor interacting protein is overexpressed in gastric cancer and promotes gastric cancer cell proliferation, migration, and invasion

“…Thus, HPIP promotes breast cancer cell growth through enhanced estrogen signaling. It also interacts with focal adhesion (FA) complex containing FA kinase (FAK), stimulates FAK, and promotes breast cancer cell migration in a FAK‐dependent manner . Hematopoietic pre‐B cell leukemia transcription factor interacting protein is also overexpressed in liver cancer patients.…”

“…(21) Improved understanding of this deadly cancer at the basic molecular level is particularly needed. Although HPIP has been shown to be involved in the development and progression of several cancers, (10)(11)(12)(13)(14) the importance of HPIP in gastric cancer is still unclear. In this study, we showed for the first time a These findings suggest that HPIP may contribute to gastric carcinogenesis and metastasis.…”

“…(9,10) It is overexpressed in breast infiltrative ductal carcinoma, astrocytoma, and oral squamous cell carcinoma, and promotes cancer cell proliferation, adhesion, and migration. (11)(12)(13) Our recent studies showed that HPIP is overexpressed in liver cancer and promotes hepatoma cell proliferation through activation of G 2 ⁄ M cell cycle transition. (14) However, the role of HPIP in gastric cancer is unclear.…”

Expression of HPIP in epithelial ovarian carcinoma: a clinicopathological study

“…Hematopoietic pre-B cell leukemia transcription factor (PBX)-interacting protein (HPIP) is a novel oncogene that is overexpressed in various human cancers, such as non-small-cell lung cancer,4 human spinal glioblastoma,5 thyroid cancer,6 gastric cancer,7 colorectal cancer,8 breast infiltrative ductal carcinoma,9 oral carcinogenesis,10 liver cancer,11 and human melanoma cell 12. Recent studies have demonstrated the multifaceted role of HPIP in pathways associated with cancer progression, including transformation, apoptosis, invasion, and metastasis 4,6,13,14.…”