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Funding
This work was supported by the Natural Science Foundations of China (81072327 and 81273114), Research Fund for the Doctoral Program of Higher Education of China (20103234110005), Key Program of Educational Commission of Jiangsu Province of China (11KJA330002), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (2010).


Conflict of interest statement


Acknowledgment


Introduction
The family of Csk-like kinases consists of two homologous enzymes—Csk and CHK. The first member identified was Csk [1], which is a kinase opposing the activation of Src kinase by phosphorylating the inhibitory Tyr527 site in this molecule [1]. We and others identified a second member of the Csk family—Csk homologous kinase (CHK), previously referred to as Matk, Ctk, Hyl, Ntk, Lsk, or Batk [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. CHK kinase is a product of the MATK gene (cytogenetic location: 19p13.3). CHK and Csk structurally share 53% amino D-Mannitol identity overall and 59% amino acid identity within the catalytic domain [5], [6], [8], [9], [10], [11]. Like Csk, CHK phosphorylates the inhibitory carboxy-terminal tyrosine of several Src-family kinases, including Lck, Fyn, c-Src, and Lyn [2], [3], [8], [9], [12]. Unlike Csk, CHK is capable of binding to some activated receptor tyrosine kinases, such as ErbB-2 (HER2) [13], [14] or TrkA [15], and of inhibiting the activation of Src following stimulation of these receptors. Importantly, contrary to Csk, which is ubiquitously expressed, the expression of CHK is limited to brain and hematopoietic cells [5], [6], [8], [9], [10], [11]. Substantial evidence supports the notion that Csk and CHK play distinct roles during development of the nervous system. However, the exact role of CHK in the nervous system is as yet unknown. In our previous studies [15], [16], using PC12 cells as well as primary hippocampal neurons as model systems, we showed that CHK participates in signaling mediated by TrkA receptors. CHK was found to be associated with tyrosine-phosphorylated TrkA receptors in PC12 cells upon stimulation with NGF. Expression of CHK resulted in enhanced activation of the mitogen-activated protein kinase/extracellular-signal-regulated kinase1/2 (MAPK, Erk1/2) pathway upon neurite growth factor (NGF) stimulation and led to neurite outgrowth in PC12 cells [17]. Of note, Csk when studied in the neuronal differentiation model of P19 cells seemed to inhibit that process [18]. Down-regulation of CHK function in PC12 cells (these cells naturally express the rat form of CHK protein), either by the microinjection of anti-CHK antibodies [15] or by treatment with antisense oligonucleotides [16], impaired the neurite outgrowth and MAPK activation stimulated by NGF. Enhancement of MAPK activity by CHK is a very interesting observation, because active Src itself was shown to induce neuronal-like differentiation via the MAPK pathway in PC12 cells [19] and both Csk and CHK elicit solely inhibitory effects toward Src kinase activity. Thus, it is not clear by which mechanism one Src-inhibiting factor (namely CHK) can stimulate neurite outgrowth through activation of MAPK, while the other (Csk) does not. We hypothesize that the effects of CHK on the MAPK pathway in PC12 cells are Src-independent and unique in comparison with Csk. Here, we evaluated this hypothesis and observed that CHK, unlike Csk, enhances MAPK activation via Ras-mediated signaling in a Src-independent manner.


Materials and methods


Results


Discussion
Csk and CHK are highly homologous enzymes and the only two kinases known to directly inhibit the function of Src-family kinases. However, while Csk is ubiquitously expressed, the expression of CHK is limited to brain and hematopoietic cells [5], [6], [8], [9], [10], [11]. Moreover, while both Csk and CHK inhibit Src-family kinases [2], [3], [8], [9], [12], only CHK enhances the activation of MAPK [15], [16], [17]. Since the pathway by which CHK is capable of activating MAPK remains virtually unknown, we attempted to elucidate this phenomenon in our studies.
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