Ntk: a Csk-related protein-tyrosine kinase expressed in brain and T lymphocytes.

Abstract

The activity of Src-related protein-tyrosine kinses is repressed by the phosphorylation of a conserved carboxyl-terminal tyrosine by another cytoplasmic proteintyrine kinase termed p50c*. In this study, we characterize Ntk, a protein-tyrouine kinase bering king smities to pO=c. Like p5Oi, Ntk Src homology 3 and Src homology 2 doma and lacks the consensus tse phosphorylation and myristoylation sites found in members of the Src family. Expression ofntk transcripts was m in brain, and was observed at signint levels in thymus and spleen. ntk RNA levels were dramatically reduced upon mitogenic stimulation of normal T lymphocytes and were minimal in transformed T-cell populations. Firm evidence that Ntk is a Cskrelated enzyme was provided by the observation that it phosphorylated a Src-related polypeptide on the inhibitory carboxyl-terminal tyrosine. These indigs indicate that Ntk is a Csk-related enzyme that may play an inhibitory role in the control of T-cell proliferation.Members of the Src family of protein-tyrosine kinases participate in a variety of signal transduction responses (for reviews, see refs. 1-3). The most convincing illustration of this role is perhaps provided by studies of intracellular signaling in T lymphocytes. In mature T cells, antigen receptor stimulation is associated with a rapid rise in intracellular protein-tyrosine phosphorylation, which is critical for subsequent T-cell mitogenesis. Because the T-cell antigen receptor lacks intrinsic catalytic properties, this biochemical signal must involve coupling to other protein-tyrosine kinases. From biochemical and genetic evidence, it is now clear that T-cell receptor signaling requires the action of Lck and FynT, two Src-related enzymes abundantly expressed in T lymphocytes.The activity of Src-related enzymes is repressed by phosphorylation of a conserved carboxyl-terminal tyrosine residue (4,5). This inhibitory phosphorylation is not a consequence of autophosphorylation but is mediated (at least in part) by a 50-kDa cytoplasmic protein-tyrosine kinase termed Csk or p5ocsk (6)(7)(8). pSOcsk is ubiquitous, but is most abundant in thymus and spleen, as well as in neonatal brain (9,10).The importance ofp5ocsk in normal cellular physiology has been documented in at least two independent systems. First, mutant mice lacking Csk have significantly altered development of the nervous system, which is associated with early embryonic lethality (11,12). Second, in antigen-specific T-lymphocyte lines, overexpression of Csk negatively regulates T-cell responsiveness following antigen receptor stimulation (13).The exon-intron structure of the csk gene differs significantly from that of other protein-tyrosine kinase genes (14).Based on this finding, as well as on the unique structural and biochemical properties of its product, the csk gene has been considered to be the sole member of a distinct family. This view is further supported by the fact that previous attempts to identify additional csk-like genes by cross hybridization under low-stringency cond...

Selected glimpses into the activation and function of Src kinase

“…A protein related to CSK has also been cloned by a number of groups (Klages et al, 1994) and is also able to regulate Src activity by phosphorylation of Tyr(527/ 530) (Chow et al, 1994;Sakano et al, 1994;Bennett et al, 1994;McVicar et al, 1994). Initially, some confusion arose because it wasn't readily apparent whether all of these cloned proteins were derived from the same gene.…”

Mice lacking a functional CHK gene have no apparent defects in the hematopoietic system

“…Fax: 7-095-135-1405, phone: 7-095-135-9855, E-mail: samoxval@imb.imb.ac.ru the tyrosine kinase Src in vitro (5). While csk is expressed ubiquitously (6), chk expression is more restricted and detected predominantly in adult brain and in hematopoietic cells of bone marrow (BM), spleen and thymus (3,7). A truncated chk transcript composed of sequences encoding the catalytic domain was also found to be expressed in the germ cells of the testis (7).…”

Vertebrate non‐receptor protein–tyrosine kinase families

“…Three were cloned from human sources; Hyl from a megakaryoblastic cell line UT-7 (Sakano et al 1994), Matk from a megakaryocytic cell line CMK (Bennett et al 1994), and Lsk from T cells (McVicar et al 1994). Two were from mouse: Ctk from brain (Klages et al 1994) and Ntk from foetal thymus (Chow et al 1994b); and Batk was isolated from rat hippocampus (Kuo et al 1994).…”

“…In vitro evidence suggests that the p52 form of Ctk can phosphorylate Lck and probably Fyn on their C-terminal tyrosines in vitro (Klages et al 1994), while the p56 form can phosphorylate both Lck (Chow et al 1994b) and Src (Avraham et al 1995). The p52 form of Ctk is maximally expressed in brain, with lower levels in spleen, thymus, and a variety of normal haemopoietic cells such as T-cells, Bcells, NK cells and bone marrow cells (Chow et al 1994a).…”