SH4-domain-induced plasma membrane dynamization promotes bleb-associated cell motility.
SH4 domains provide bipartite membrane-targeting signals for oncogenic Src family kinases. Here we report the induction of non-apoptotic plasma membrane (PM) blebbing as a novel and conserved activity of SH4 domains derived from the prototypic Src kinases Src, Fyn, Yes and Lck as well as the HASPB protein of Leishmania parasites. SH4-domain-induced blebbing is highly dynamic, with bleb formation and collapse displaying distinct kinetics. These reorganizations of the PM are controlled by Rho but not Rac or Cdc42 GTPase signalling pathways. SH4-induced membrane blebbing requires the membrane association of the SH4 domain, is regulated by the activities of Rock kinase and myosin II ATPase, and depends on the integrity of F-actin as well as microtubules. Endogenous Src kinase activity is crucial for PM blebbing in SH4-domain-expressing cells, active Src and Rock kinases are enriched in SH4-domain-induced PM blebs, and PM blebbing correlates with enhanced cell invasion in 3D matrices. These results establish a novel link between SH4 domains, Src activity and Rho signalling, and implicate SH4-domain-mediated PM dynamization as a mechanism that influences invasiveness of cells transformed by SH4-domain-containing oncoproteins.
Tournaviti
Stella
S
Heidelberg University Biochemistry Center, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
Hannemann
Sebastian
S
Terjung
Stefan
S
Kitzing
Thomas M
TM
Stegmayer
Carolin
C
Ritzerfeld
Julia
J
Walther
Paul
P
Grosse
Robert
R
Nickel
Walter
W
Fackler
Oliver T
OT
D020816:Amino Acid Motifs; D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics / Q000378:metabolism; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002465:Cell Movement / Q000502:physiology*; D022081:Cell Surface Extensions / Q000378:metabolism / Q000648:ultrastructure; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D006801:Humans; D007891:Leishmania / Q000378:metabolism / Q000472:pathogenicity; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
D000953:Antigens, Protozoan; C401884:HASPB protein, Leishmania; D018994:Myosin Light Chains; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; D019061:src-Family Kinases; D020741:rho GTP-Binding Proteins