Rab25 associates with alpha5beta1 integrin to promote invasive migration in 3D microenvironments.
Here, we report a direct interaction between the beta1 integrin cytoplasmic tail and Rab25, a GTPase that has been linked to tumor aggressiveness and metastasis. Rab25 promotes a mode of migration on 3D matrices that is characterized by the extension of long pseudopodia, and the association of the GTPase with alpha5beta1 promotes localization of vesicles that deliver integrin to the plasma membrane at pseudopodial tips as well as the retention of a pool of cycling alpha5beta1 at the cell front. Furthermore, Rab25-driven tumor-cell invasion into a 3D extracellular matrix environment is strongly dependent on ligation of fibronectin by alpha5beta1 integrin and the capacity of Rab25 to interact with beta1 integrin. These data indicate that Rab25 contributes to tumor progression by directing the localization of integrin-recycling vesicles and thereby enhancing the ability of tumor cells to invade the extracellular matrix.
Caswell
Patrick T
PT
Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
Spence
Heather J
HJ
Parsons
Maddy
M
White
Dominic P
DP
Clark
Katherine
K
Cheng
Kwai Wa
KW
Mills
Gordon B
GB
Humphries
Martin J
MJ
Messent
Anthea J
AJ
Anderson
Kurt I
KI
McCaffrey
Mary W
MW
Ozanne
Bradford W
BW
Norman
Jim C
JC
D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002522:Chlorocebus aethiops; D003094:Collagen; D004338:Drug Combinations; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism / Q000502:physiology*; D007797:Laminin; D051379:Mice; D009361:Neoplasm Invasiveness; D021381:Protein Transport; D011509:Proteoglycans; D011554:Pseudopodia / Q000378:metabolism; D051381:Rats; D020691:rab GTP-Binding Proteins / Q000502:physiology*
D004338:Drug Combinations; D039081:Integrin alpha5beta1; D007797:Laminin; D011509:Proteoglycans; C509763:Rab25 protein, human; C059485:matrigel; D003094:Collagen; D020691:rab GTP-Binding Proteins