Disease relevance of Crk

• Isoflurane preconditioning induces neuroprotection against ischemia via activation of P38 mitogen-activated protein kinases [1].
• P38 mitogen-activated protein kinase inhibition attenuates ischemia-reperfusion injury of the rat liver [2].
• These results suggest that Kuppfer cells can reverse liver fibrosis via the expression of MMPs mainly through P38 pathway [3].
• Between the ages of P7-P38, P2 receptor damage lowers ganglion concentration of an acidic membrane glycoprotein designated as A1, with an apparent M(r) of 64-67 kDa and a pI of 4.8-5.2 P2 receptor damage also lowers ganglion concentrations of GAP-43 [4].
• Recombinant constitutively active adenovirus (Ad)-MKK6 and-MKK7 increased TNF-alpha production in KCs with activation of P38 and JNK without any change by Ad-MEK1 delivery [5].

High impact information on Crk

• With these findings, we designate pp105 as Cas-L, lymphocyte-type Cas. Furthermore, we demonstrate that integrin/ligand binding results in the recruitment of Crk, Nck, and SHPTP2 to pp105 [6].
• Tumor necrosis factor alpha-induced PPAR-beta phosphorylation and expression was evaluated by metabolic labeling and by using specific P38 inhibitors [7].
• Tyrosine 221 in Crk regulates adhesion-dependent membrane localization of Crk and Rac and activation of Rac signaling [8].
• Overexpression of wild-type paxillin or Crk could bypass the migration-deficient phenotype [9].
• This v-Crk-dependent formation of microvilli was suppressed by inhibitors of Rho-associated kinase, and the activity of RhoA was elevated by coexpression of c-Crk-II and ERMs in 3Y1 cells [10].

Biological context of Crk

• To further explore the role of Crk in NGF-induced PC-12 cell differentiation, we found that both NGF and epidermal growth factor stimulate the tyrosine phosphorylation of endogenous Crk II [11].
• This interaction is mediated by the SH2 domain of Crk and can be inhibited with a phosphopeptide containing the Crk-SH2 binding motif [11].
• The signaling adaptor protein Crk has been shown to regulate cell motility, but its precise role is still under investigation [10].
• The Crk family of adaptor proteins participate in diverse signaling pathways that regulate growth factor-induced proliferation, anchorage-dependent DNA synthesis, and cytoskeletal reorganization, important for cell adhesion and motility [12].
• c-SRC mediates neurite outgrowth through recruitment of Crk to the scaffolding protein Sin/Efs without altering the kinetics of ERK activation [13].

Anatomical context of Crk

• The binding of Crk with ERMs was demonstrated both by transient and stable protein expression systems in 293T cells and 3Y1 cells, and it was shown that v-Crk translocated the phosphorylated form of ERMs to microvilli in 3Y1 cells by immunofluorescence and immunoelectron microscopy [10].
• The cellular homologs of the v-Crk oncogene product consist primarily of Src homology region 2 (SH2) and 3 (SH3) domains. v-Crk overexpression causes cell transformation and elevation of tyrosine phosphorylation in fibroblasts and accelerates differentiation of PC-12 cells in response to nerve growth factor (NGF) [11].
• In addition, Crk becomes phosphorylated on tyrosine and serine following EGF treatment of PC12 and other cell lines [14].
• However, the precise mechanism of Crk-dependent regulation of cytoskeleton still remains under investigation [15].
• The adaptor protein Crk has been reported to associate with focal adhesions and is thought to be involved in integrin-mediated signaling pathway [15].

Associations of Crk with chemical compounds

• These results suggest that Crk may be involved in regulation of cell motility by a hyaluronic acid-dependent mechanism through an association with ERMs [10].
• Moreover, hormone stimulation enhanced the specific association of Crk proteins with the tyrosine-phosphorylated p130Cas, the major phosphotyrosine-containing protein in cells transformed with v-Crk [11].
• CONCLUSION: beta cells contain the SH2-containing adapter protein Crk, which undergoes glucose-induced association with p130Cas [16].
• The binding of two guanine nucleotide exchange factors, Sos and C3G, to Crk and CRKL indicates that Ras or related proteins likely play a role in signaling through Crk family proteins [17].
• It was found in complexes with many signaling proteins, including phosphoinositol (PtdIns) 3-kinase (EC 2.7.1.137), Cbl, GRB2, p130Cas and Crk [18].

Physical interactions of Crk

• Whereas previous studies have shown that Crk SH2 binding to paxillin is critical for cell adhesion and migration, our data show that the phosphorylation cycle of c-Crk II determines its dynamic interaction with paxillin, thereby regulating turnover of multiprotein complexes, a critical aspect of cytoskeletal plasticity and actin dynamics [12].

Other interactions of Crk

• Moreover, Crk together with Dock180 were present at the filopodial tips of beta1B-integrin-expressing cells, and there was a prominent Rac1 activation [19].
• However, both forms could associate with Csk and Crk [20].
• Collectively, the focal adhesion-dependent p130Cas/Crk/Pyk2/c-Src-mediated pathway is selectively involved in ET-induced JNK activation in cardiomyocytes [21].
• The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk [22].
• Overlay analyses and affinity chromatography with glutathione S-transferase (GST) fusion proteins of Src homology-3 (SH3) domains showed direct binding of the Src but not the Crk SH3 domain to p58gag [23].

Analytical, diagnostic and therapeutic context of Crk

• In contrast, little or no rescue was observed in the retinas of those RCS dystrophic rats when RPE cell transplantation was performed at P38, P43 and P48 [24].
• P38 mitogen-activated protein kinase inhibition attenuates pulmonary inflammatory response in a rat cardiopulmonary bypass model [25].
• According to Western blotting analysis and immunohistochemical and morphological observations, laminin not only retains SMCs in a contractile state but also possibly stimulates cells to transform a synthetic to a contractile phenotype at an early stage, mediated by P38 MAPK signal transduction [26].
• A higher degree of expression of all the three classes of MAPK, i.e. JNK, P38 MAP kinases and P-extracellular signal regulated kinases (ERKs) can be seen in kidneys subjected to ischemia/reperfusion insult [27].

References