5'-Inositol phosphatase SHIP2 recruits Mena to stabilize invadopodia for cancer cell invasion.
Invadopodia are specialized membrane protrusions that support degradation of extracellular matrix (ECM) by cancer cells, allowing invasion and metastatic spread. Although early stages of invadopodia assembly have been elucidated, little is known about maturation of invadopodia into structures competent for ECM proteolysis. The localized conversion of phosphatidylinositol(3,4,5)-triphosphate and accumulation of phosphatidylinositol(3,4)-bisphosphate at invadopodia is a key determinant for invadopodia maturation. Here we investigate the role of the 5'-inositol phosphatase, SHIP2, and reveal an unexpected scaffold function of SHIP2 as a prerequisite for invadopodia-mediated ECM degradation. Through biochemical and structure-function analyses, we identify specific interactions between SHIP2 and Mena, an Ena/VASP-family actin regulatory protein. We demonstrate that SHIP2 recruits Mena, but not VASP, to invadopodia and that disruption of SHIP2-Mena interaction in cancer cells leads to attenuated capacity for ECM degradation and invasion in vitro, as well as reduced metastasis in vivo. Together, these findings identify SHIP2 as a key modulator of carcinoma invasiveness and a target for metastatic disease.
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada Department of Biochemistry, McGill University, Montréal, Québec H3A 1A1, Canada.
Charles V
0000-0001-8067-3376
CV
Rajadurai
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada.
Serhiy
0000-0001-8952-2523
S
Havrylov
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada Department of Biochemistry, McGill University, Montréal, Québec H3A 1A1, Canada.
Paula P
0000-0002-7006-4523
PP
Coelho
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada Department of Biochemistry, McGill University, Montréal, Québec H3A 1A1, Canada.
Colin D H
0000-0003-4707-8326
CD
Ratcliffe
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada.
Kossay
K
Zaoui
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada Department of Biochemistry, McGill University, Montréal, Québec H3A 1A1, Canada.
Bruce H
BH
Huang
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada.
Anie
0000-0002-0774-0090
A
Monast
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada.
Naila
0000-0001-7262-3758
N
Chughtai
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada Department of Oncology, McGill University, Montréal, Québec H3A 1A1, Canada.
Veena
V
Sangwan
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Frank B
FB
Gertler
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada Department of Biochemistry, McGill University, Montréal, Québec H3A 1A1, Canada Department of Medicine, McGill University, Montréal, Québec H3A 1A1, Canada.
Peter M
0000-0002-5568-6586
PM
Siegel
Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A1, Canada Department of Biochemistry, McGill University, Montréal, Québec H3A 1A1, Canada Department of Medicine, McGill University, Montréal, Québec H3A 1A1, Canada Department of Oncology, McGill University, Montréal, Québec H3A 1A1, Canada morag.park@mcgill.ca.
Morag
0000-0001-5400-606X
M
Park
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D000069261:Podosomes / Q000201:enzymology* / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; C511939:Enah protein, human; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases