title: 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.
authors.affiliation: Molecular and Cellular Oncology Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: S
authors.initials: S
authors.lastname: Bugide
authors.affiliation: Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.
authors.forename: D
authors.initials: D
authors.lastname: David
authors.affiliation: Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.
authors.forename: A
authors.initials: A
authors.lastname: Nair
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Kannan
authors.affiliation: Molecular and Cellular Oncology Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: V S K
authors.initials: VS
authors.lastname: Samanthapudi
authors.affiliation: Regional Cancer Centre, Thiruvananthapuram, India.
authors.forename: J
authors.initials: J
authors.lastname: Prabhakar
authors.affiliation: Molecular and Cellular Oncology Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India.
authors.forename: B
authors.initials: B
authors.lastname: Manavathi
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002465:Cell Movement; D004789:Enzyme Activation; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational
chemical_list: C469750:HCFC1R1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases; D002154:Calpain; C569870:CAPN2 protein, human