NPM-ALK phosphorylates WASp Y102 and contributes to oncogenesis of anaplastic large cell lymphoma.
Mechanisms by which NPM-ALK signaling regulates cell migration, invasion and contributes to the oncogenesis of anaplastic large cell lymphoma (ALCL) are not completely understood. In an attempt to identify novel actin signaling pathways regulated by NPM-ALK, a comprehensive phosphoproteome analysis of ALCL cell lines was performed in the presence or absence of NPM-ALK activity. Numerous phosphoproteins involved in actin dynamics including Wiskott-Aldrich syndrome protein (WASp) were regulated by NPM-ALK. Network analysis revealed that WASp is a central component of the NPM-ALK-dependent actin signaling pathway. Here we show that NPM-ALK phosphorylates WASp at its known activation site (Y290) as well as at a novel residue (Y102). Phosphorylation of WASp at Y102 negatively regulates its interaction with Wiskott-Aldrich interacting protein and decreases its protein stability. Phosphorylation of WASp at Y102 enhances anchorage-independent growth and tumor growth in an in vivo xenograft model and enhances invasive properties of ALCL. We show that knock-down of WASp or expression of Y102F mutant of WASp decreases colony formation and in vivo tumor growth. Our results show that WASp is a novel substrate of ALK and has a critical role in regulating invasiveness and oncogenesis of ALCL.
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
C A
CA
Murga-Zamalloa
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
V
V
Mendoza-Reinoso
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
A A
AA
Sahasrabuddhe
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
D
D
Rolland
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
S R
SR
Hwang
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
S R P
SR
McDonnell
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
A P
AP
Sciallis
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
R A
RA
Wilcox
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
V
V
Bashur
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
K
K
Elenitoba-Johnson
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
M S
MS
Lim
D000818:Animals; D063646:Carcinogenesis; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism*
C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases
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