Pak2 is required for actin cytoskeleton remodeling, TCR signaling, and normal thymocyte development and maturation.
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.DOI: http://dx.doi.org/10.7554/eLife.02270.001.
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, United States hyewon.phee@northwestern.edu.
Hyewon
H
Phee
Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, United States.
Byron B
BB
Au-Yeung
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, United States.
Olga
O
Pryshchep
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, United States.
Kyle Leonard
KL
O'Hagan
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, United States.
Stephanie Grace
SG
Fairbairn
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, United States.
Maria
M
Radu
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, United States.
Rachelle
R
Kosoff
Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, United States.
Marianne
M
Mollenauer
Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, United States.
Debra
D
Cheng
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, United States.
Jonathan
J
Chernoff
Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, United States Rosalind Russell Medical Research Center for Arthritis, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States.
Arthur
A
Weiss
D008841:Actin Cytoskeleton / Q000502:physiology*; D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D060168:Thymocytes / Q000166:cytology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000502:physiology*
D011948:Receptors, Antigen, T-Cell; C515909:Pak2 protein, mouse; D054462:p21-Activated Kinases
T cell development; p21-activated kinase; signal transduction