Pak2 is required for actin cytoskeleton remodeling, TCR signaling, and normal thymocyte development and maturation

• Type of Material: Article
• Authors: Hyewon Phee, Northwestern University; Byron Au-Yeung, Emory University; Olga Pryshchep, Northwestern University; Kyle Leonard O'Hagan, Northwestern University; Stephanie Grace Fairbairn, Northwestern University; Maria Radu, Fox Chase Cancer Center; Rachelle Kosoff, Fox Chase Cancer Center; Marianne Mollenauer, University of California San Francisco; Debra Cheng, University of California San Francisco; Jonathan Chernoff, Fox Chase Cancer Center; Arthur Weiss, University of California San Francisco
• Language: English
• Date: 2014-05-13
• Publisher: eLife Sciences Publications
• Publication Version: Final Published Version
• Copyright Statement: © Phee et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.7554/eLife.02270
• Title of Journal or Parent Work: eLife
• ISSN: 2050-084X
• Volume: 3
• Issue: 3
• Start Page: e02270
• End Page: e02270
• Grant/Funding Information: This work was supported grants from US National Institutes of Health 5K01AR059754 (HP) and R01 CA142928 (JC), as well as the Howard Hughes Medical Institute (AW).
• Keywords: POSITIVE SELECTION; NEGATIVE SELECTION; T-CELL-RECEPTOR; THYMIC EMIGRATION; Biology; VAV-FAMILY PROTEINS; BETA-CHAIN GENES; F-ACTIN; Science & Technology; NUCLEOTIDE EXCHANGE FACTOR; KRUPPEL-LIKE FACTOR-2; LYMPHOCYTE DEVELOPMENT; Life Sciences & Biomedicine - Other Topics; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology

Abstract

The molecular mechanisms that govern thymocyte development and maturation are incompletely understood. The P21-activated kinase 2 (Pak2) is an effector for the Rho family GTPases Rac and Cdc42 that regulate actin cytoskeletal remodeling, but its role in the immune system remains poorly understood. In this study, we show that T-cell specific deletion of Pak2 gene in mice resulted in severe T cell lymphopenia accompanied by marked defects in development, maturation, and egress of thymocytes. Pak2 was required for pre-TCR β-selection and positive selection. Surprisingly, Pak2 deficiency in CD4 single positive thymocytes prevented functional maturation and reduced expression of S1P1 and KLF2. Mechanistically, Pak2 is required for actin cytoskeletal remodeling triggered by TCR. Failure to induce proper actin cytoskeletal remodeling impaired PLCγ1 and Erk1/2 signaling in the absence of Pak2, uncovering the critical function of Pak2 as an essential regulator that governs the actin cytoskeleton-dependent signaling to ensure normal thymocyte development and maturation.