Suppressor of Cytokine Signaling 2 Regulates IL-15–Primed Human NK Cell Function via Control of Phosphorylated Pyk2

Abstract

NK cells are capable of killing virus-infected or tumor cells and producing IFN-γ. Resting NK cells, however, have only minimal cytolytic activity and secrete a low level of IFN-γ. The cytokine IL-15 can promote the expression of effector functions by resting NK cells. In this study, we demonstrate that suppressor of cytokine signaling 2 (SOCS2) has a novel role in IL-15–primed human NK cell function. SOCS2 expression was upregulated in NK cells following stimulation with IL-15. During IL-15–mediated NK cell priming, SOCS2 interacted with phosphorylated proline-rich tyrosine kinase 2 (Pyk2) at tyrosine 402 (p-Pyk2Tyr402) and induced the proteasome-mediated degradation of p-Pyk2Tyr402 via ubiquitination. Knockdown of SOCS2 resulted in the accumulation of p-Pyk2Tyr402 and blocked NK cell effector functions. In addition, NK cell cytolytic activity and IFN-γ production were inhibited by overexpression of the wild-type of Pyk2 but not by the overexpression of tyrosine 402 mutant of Pyk2. These results suggest that SOCS2 regulates human NK cell effector functions via control of phosphorylated Pyk2 depending on IL-15 existence.

Megakaryocytes Regulate Expression of Pyk2 Isoforms and Caspase-mediated Cleavage of Actin in Osteoblasts

“…Recently published studies suggest that Pyk2 undergoes proteosome-mediated degradation (48). Therefore, the transient decrease in Pyk2 in OBs co-cultured with MKs could potentially be due to changes in the stability or degradation of Pyk2.…”

The SOCS box—Adapting proteins for ubiquitination and proteasomal degradation

“…Deletion of the SOCS2-SOCS box abrogates regulation of GH signalling, with SOCS2 shown to have E3 ligase activity, ubiquitinating the GHR in vitro (34,42). SOCS2 has also been shown to bind phosphorylated Pyk2 in NK cells, and this interaction correlates with decreased Pyk2 levels (43).…”

SOCS2 Controls Proliferation and Stemness of Hematopoietic Cells under Stress Conditions and Its Deregulation Marks Unfavorable Acute Leukemias

“…SOCS1 and SOCS3 immunologic roles are widely recognized (6,7). SOCS2 has been initially described as a regulator of the growth hormoneinsulin-like growth factor 1 axis (8,9) and only recently has been recognized as controller of immunologic functions (10)(11)(12). SOCS2 basal expression is higher in HSC (particularly LT-HSC) than in differentiated populations (13)(14)(15)(16), and it is upregulated following STAT5 activation by hematopoietic cytokine stimulation (17) or following myeloablative 5-fluorouracil (5-FU) treatment (18).…”

“…In hematologic malignancies (20)(21)(22), the JAK-STAT pathways are frequently deregulated (10,11), with oncogenic activation of STAT3 and STAT5 in acute myeloid leukemia (AML), and of STAT1 and STAT5 in pre-B acute lymphoblastic leukemia (B-ALL) and chronic myelogenous leukemia (CML; ref. 20), with potential involvement of SOCS2.…”