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NPM-ALK phosphorylates WASp Y102 and contributes to oncogenesis of anaplastic large cell lymphoma
C A Murga-Zamalloa1, V Mendoza-Reinoso1, A A Sahasrabuddhe1
1Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Abstract:
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.
Insights
NPM-ALK signaling drives anaplastic large cell lymphoma (ALCL) oncogenesis by phosphorylating Wiskott-Aldrich syndrome protein (WASp). This phosphorylation enhances tumor invasiveness and growth, identifying WASp as a key ALK target in ALCL.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- The role of NPM-ALK signaling in anaplastic large cell lymphoma (ALCL) oncogenesis, particularly in regulating cell migration and invasion, remains incompletely understood.
- Identifying novel signaling pathways controlled by NPM-ALK is crucial for understanding ALCL pathogenesis.
Purpose of the Study:
- To investigate novel actin signaling pathways regulated by NPM-ALK in ALCL.
- To elucidate the role of Wiskott-Aldrich syndrome protein (WASp) as a downstream effector of NPM-ALK signaling in ALCL.
Main Methods:
- Comprehensive phosphoproteome analysis of ALCL cell lines with and without NPM-ALK activity.
- Network analysis to identify central components in NPM-ALK-dependent actin signaling.
- In vitro and in vivo experiments using WASp knockdown and mutant variants.
Main Results:
- NPM-ALK regulates numerous phosphoproteins involved in actin dynamics, notably WASp.
- NPM-ALK phosphorylates WASp at both a known (Y290) and a novel (Y102) site.
- Phosphorylation at Y102 negatively impacts WASp-interacting protein binding and protein stability, while enhancing anchorage-independent growth, tumor growth, and ALCL invasiveness.
Conclusions:
- WASp is a novel substrate of ALK, playing a critical role in ALCL invasiveness and oncogenesis.
- Targeting WASp phosphorylation or its interaction with ALK may offer therapeutic strategies for ALCL.
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