WIP regulates the stability and localization of WASP to podosomes in migrating dendritic cells.
The Wiskott-Aldrich Syndrome protein (WASP) is an adaptor protein that is essential for podosome formation in hematopoietic cells. Given that 80% of identified Wiskott-Aldrich Syndrome patients result from mutations in the binding site for WASP-interacting-protein (WIP), we examined the possible role of WIP in the regulation of podosome architecture and cell motility in dendritic cells (DCs). Our results show that WIP is essential both for the formation of actin cores containing WASP and cortactin and for the organization of integrin and integrin-associated proteins in circular arrays, specific characteristics of podosome structure. We also found that WIP is essential for the maintenance of the high turnover of adhesions and polarity in DCs. WIP exerts these functions by regulating calpain-mediated cleavage of WASP and by facilitating the localization of WASP to sites of actin polymerization at podosomes. Taken together, our results indicate that WIP is critical for the regulation of both the stability and localization of WASP in migrating DCs and suggest that WASP and WIP operate as a functional unit to control DC motility in response to changes in the extracellular environment.
Chou
Hsiu-Chuan
HC
Randall Division of Cell & Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom.
Antón
Inés M
IM
Holt
Mark R
MR
Curcio
Claudia
C
Lanzardo
Stefania
S
Worth
Austen
A
Burns
Siobhan
S
Thrasher
Adrian J
AJ
Jones
Gareth E
GE
Calle
Yolanda
Y
D000199:Actins / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002448:Cell Adhesion; D002465:Cell Movement; D016764:Cell Polarity; D022081:Cell Surface Extensions / Q000378:metabolism*; D051356:Cortactin / Q000502:physiology; D003598:Cytoskeletal Proteins; D003713:Dendritic Cells / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020298:U937 Cells; D051316:Wiskott-Aldrich Syndrome Protein / Q000737:chemistry / Q000378:metabolism*
D000199:Actins; D002352:Carrier Proteins; D051356:Cortactin; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C109903:WIPF1 protein, human; D051316:Wiskott-Aldrich Syndrome Protein