Loss of ADAM9 expression impairs β1 integrin endocytosis, focal adhesion formation and cancer cell migration

TY - JOUR

T1 - Loss of ADAM9 expression impairs β1 integrin endocytosis, focal adhesion formation and cancer cell migration

AU - Mygind, Kasper J

AU - Schwarz, Jeanette

AU - Sahgal, Pranshu

AU - Ivaska, Johanna

AU - Kveiborg, Marie

N1 - © 2018. Published by The Company of Biologists Ltd.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - The transmembrane protease ADAM9 is frequently upregulated in human cancers, and it promotes tumour progression in mice.In vitro, ADAM9 regulates cancer cell adhesion and migration by interacting with integrins. However, how ADAM9 modulates integrin functions is not known. We here show that ADAM9 knockdown increases β1 integrin levels through mechanisms that are independent of its protease activity. In ADAM9-silenced cells, adhesion to collagen and fibronectin is reduced, suggesting an altered function of the accumulated integrins. Mechanistically, ADAM9 co-immunoprecipitates with β1 integrin, and both internalization and subsequent degradation of β1 integrin are significantly decreased in ADAM9-silenced cells, with no effect on β1 integrin recycling. Accordingly, the formation of focal adhesions and actin stress fibres in ADAM9-silenced cells is altered, possibly explaining the reduction in cell adhesion and migration in these cells. Taken together, our data provide mechanistic insight into the ADAM9-integrin interaction, demonstrating that ADAM9 regulates β1 integrin endocytosis. Moreover, our findings indicate that the reduced migration of ADAM9-silenced cells is, at least in part, caused by the accumulation and altered activity of β1 integrin at the cell surface.

AB - The transmembrane protease ADAM9 is frequently upregulated in human cancers, and it promotes tumour progression in mice.In vitro, ADAM9 regulates cancer cell adhesion and migration by interacting with integrins. However, how ADAM9 modulates integrin functions is not known. We here show that ADAM9 knockdown increases β1 integrin levels through mechanisms that are independent of its protease activity. In ADAM9-silenced cells, adhesion to collagen and fibronectin is reduced, suggesting an altered function of the accumulated integrins. Mechanistically, ADAM9 co-immunoprecipitates with β1 integrin, and both internalization and subsequent degradation of β1 integrin are significantly decreased in ADAM9-silenced cells, with no effect on β1 integrin recycling. Accordingly, the formation of focal adhesions and actin stress fibres in ADAM9-silenced cells is altered, possibly explaining the reduction in cell adhesion and migration in these cells. Taken together, our data provide mechanistic insight into the ADAM9-integrin interaction, demonstrating that ADAM9 regulates β1 integrin endocytosis. Moreover, our findings indicate that the reduced migration of ADAM9-silenced cells is, at least in part, caused by the accumulation and altered activity of β1 integrin at the cell surface.

U2 - 10.1242/jcs.205393

DO - 10.1242/jcs.205393

M3 - Journal article

C2 - 29142101

SN - 0021-9533

VL - 131

SP - 1

EP - 12

JO - Journal of Cell Science

JF - Journal of Cell Science

IS - 1

M1 - jcs205393

ER -