Abstract
We have previously shown that Jak3 is involved in the signaling pathways of CCR7, CCR9 and CXCR4 in murine T lymphocytes and that Jak3−/− lymphocytes display an intrinsic defect in homing to peripheral lymph nodes. However, the molecular mechanism underlying the defective migration observed in Jak3−/− lymphocytes remains elusive. Here, it is demonstrated for the first time, that Jak3 is required for the actin cytoskeleton reorganization in T lymphocytes responding to chemokines. It was found that Jak3 regulates actin polymerization by controlling cofilin inactivation in response to CCL21 and CXCL12. Interestingly, cofilin inactivation was not precluded in PTX- treated cells despite their impaired actin polymerization. Additionally, Jak3 was required for small GTPases Rac1 and RhoA activation, which are indispensable for acquisition of the migratory cell phenotype and the generation of a functional leading edge and uropod, respectively. This defect correlates with data obtained by time-lapse video-microscopy showing an incompetent uropod formation and impaired motility in Jak3-pharmacologically inhibited T lymphocytes. Our data support a new model in which Jak3 and heterotrimeric G proteins can use independent, but complementary, signaling pathways to regulate actin cytoskeleton dynamics during cell migration in response to chemokines.
Highlights
T lymphocyte development, tissue localization, cellular proliferation and migration are mainly orchestrated by chemokines
We show for the first time that Jak3 is required for actin cytoskeleton rearrangement in response to CXCL12 and CCL21 and that Jak3, but not G proteins, regulates cofilin-mediated actin dynamics, as inhibition of Jak3, but not of G proteins, results in sustained cofilin activation
Cofilin modulates F-actin reorganization, while GTPases Rac and RhoA participate in the organization of actin filaments to generate lamellipodia and uropods, two characteristic structures of the migratory phenotype
Summary
T lymphocyte development, tissue localization, cellular proliferation and migration are mainly orchestrated by chemokines. These processes are crucial during basal traffic to secondary lymphoid organs and homing to sites of inflammation during the course of an immune response [1]. Chemokines interact with seven transmembrane domain G protein-coupled receptors (GPCR) and trigger several signaling pathways leading to activation of gene transcription, reorganization of the cytoskeleton and cell migration. It has been extensively demonstrated that chemokine receptors (CCRs) transduce their signals by coupling to Gai proteins, as pertussis toxin (PTX) inhibits most chemokine-mediated responses. Upon GPCR activation, heterotrimeric G proteins are dissociated into Ga and Gbc subunits that initiate different signaling pathways (reviewed in [2]). Bc subunits phosphorylate PI3 kinase and downstream effectors, including small GTPases (Rac, Rho, Cdc42), guanine nucleotide exchange factor GEFVav, and focal adhesion kinases, all of them involved in cytoskeleton rearrangements that are required for cell adhesion and migration (reviewed in [3])
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