HS1-associated protein X-1 regulates carcinoma cell migration and invasion via clathrin-mediated endocytosis of integrin alphavbeta6.
Enhanced expression levels of integrin alphavbeta6 have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how alphavbeta6 determines invasion and the dynamics of integrin alphavbeta6 regulation in tumor cells are poorly understood. We have identified the 35-kDa HS1-associated protein X-1 (HAX-1) protein as a novel binding partner of the beta6 cytoplasmic tail using a yeast two-hybrid screen. We show that alphavbeta6-dependent migration is blocked following small interfering RNA (siRNA)-mediated depletion of HAX-1 in oral squamous cell carcinoma cell lines. Using both siRNA and membrane-permeable peptides, we show that alphavbeta6-dependent migration and invasion require HAX-1 to bind directly to beta6 and thereby regulate clathrin-mediated endocytosis of alphavbeta6 integrins. Progression of oral cancer is associated with enhanced expression of alphavbeta6 and HAX-1 proteins in patient tissue. This report establishes that integrin endocytosis is required for alphavbeta6-dependent carcinoma cell motility and invasion and suggests that this process is an important mechanism in cancer progression.
Ramsay
Alan G
AG
Centre for Tumour Biology, Institute of Cancer and Cancer Research UK Clinical Centre, London, United Kingdom.
Keppler
Melanie D
MD
Jazayeri
Mona
M
Thomas
Gareth J
GJ
Parsons
Maddy
M
Violette
Shelia
S
Weinreb
Paul
P
Hart
Ian R
IR
Marshall
John F
JF
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002463:Cell Membrane Permeability; D002465:Cell Movement / Q000502:physiology*; D002966:Clathrin / Q000378:metabolism*; D015536:Down-Regulation; D004705:Endocytosis; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; D002966:Clathrin; C104759:HAX1 protein, human; D016023:Integrins; D010455:Peptides; D011506:Proteins; D034741:RNA, Small Interfering; C073878:integrin alphavbeta6