Expression of a Truncated Form of the c-Kit Tyrosine Kinase Receptor and Activation of Src Kinase in Human Prostatic Cancer

Abstract

The c-Kit receptor belongs to type III tyrosine kinase receptor, which consists of an extracellular ligand binding domain and an intracellular kinase domain. In the kinase domain, the ATP binding site is separated from the phosphotransferase site by an interkinase sequence required for interaction with signal transduction proteins involved in the c-Kit pathway. 1 The c-Kit receptor is expressed in a wide variety of normal and neoplastic tissues. A positive correlation between misregulation of the c-kit gene and malignant transformation of cells has been reported. 2,3 For instance, substitution mutations in exon 11 of the gene, changing amino acids of the juxtamembrane region of the receptor, are associated with gastrointestinal stromal tumors, whereas mutations in exon 17 that substitute Asp816, just downstream of the tyrosine kinase signature, are associated with myeloid leukemias and testicular seminomas. 2,3 These mutations induce ligand-independent dimerization or autophosphorylation of the receptor and they cause constitutive activation of downstream signaling pathways. Moreover, overexpression of c-Kit and its ligand SCF occurs in several tumors and they probably stimulate proliferation in an autocrine or paracrine manner. 2 Recently, c-kit expression in various tumors has been revisited because this receptor is a target of the anti-cancer activity of a well described tyrosine kinase inhibitor: imatinib (STI1571). 2,4 Beside mutations affecting the activity of the full-length c-Kit, expression of an alternative transcript of human c-kit has been described in several transformed cell lines. The

Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer

“…Deregulation of these miRNAs may cause defects in cell cycle checkpoint control and further promote cell cycle progression by decreasing the expression levels of tumor suppressors PTEN, p21 and Rb1, which are commonly inactivated in PCa (reviewed by Lee et al, 2008). In addition, decreased expression of miR-27, miR-143 and miR-221/222 may promote increased expression of Notch1, MAPK kinases and c-KIT, which have been associated with epithelialmesenchymal transition, angiogenesis and metastasis in PCa (Paronetto et al, 2004;Bin Hafeez et al, 2009;Mukherjee et al, 2011).…”

The RNA-binding protein Sam68 is a multifunctional player in human cancer

“…These apparently conflicting results can be reconciled by the observation that tyrosine phosphorylation of Sam68 by Src-like kinases reverts BCL-X splicing and promotes the anti-apoptotic BCL-X L variant ), thereby inhibiting cell death (Brignatz et al 2009). Interestingly, Src activity is often increased in cancer cells (Irby & Yeatman 2000), and it correlates with Sam68 phosphorylation in prostate and breast carcinomas (Paronetto et al 2004, Lukong et al 2005. Therefore, tyrosine phosphorylation of Sam68 in cancer cells may represent a mechanism to protect them from apoptosis by altering the BCL-X S /BCL-X L ratio ; Fig.…”

“…Assembly of the Sam68/PLCg1/Fyn complex was stimulated by expression of a truncated form of the tyrosine kinase receptor c-KIT. Notably, this truncated receptor is aberrantly expressed in a subgroup of prostate cancer (PCa) patients, and its expression correlates with enhanced activation of Src and tyrosine phosphorylation of Sam68 (Paronetto et al 2004), suggesting that this pathway is involved in Srcmediated tumorigenesis in the prostate.…”

“…Furthermore, as reported in the previous sections, a number of experimental observations suggest a direct involvement of Sam68 in oncogenesis, through regulation of signal transduction pathways and modulation of gene expression, especially in endocrine-related cancers. For instance, Src activation by a truncated c-Kit receptor stimulates Sam68 phosphorylation in cultured cells and in PCa patients (Paronetto et al 2003(Paronetto et al , 2004. Since tyrosine phosphorylation by Src-related kinases fine-tunes Sam68-mediated splicing and apoptosis , Brignatz et al 2009, and Src is often activated in human cancers (Biscardi et al 2000, Irby & Yeatman 2000, this mechanism might promote survival of neoplastic cells.…”

Combination of axitinib and dasatinib for anti-cancer activities in two prostate cancer cell lines

“…The onset and progression of PCa correlated with c-KIT receptor (Paronetto et al, 2004) however, the expression of c-KIT isoforms in PCa cells is still unknown and needs further exploration. Therefore, the full-length c-KIT and its small isoforms expression were studied in PPC-1 and TSU-Pr1 cells.…”