Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The insulin receptor substrate (IRS) family plays important roles in cellular growth, signaling, and survival in the brain. We identified IRS6/Dok-5, a member of the IRS family, also expressed in heart. Dok-5 expression level significantly increased during cardiomyocyte differentiation of P19CL6 cells. To understand the mechanism of Dok-5 gene expression and regulation during cardiomyocyte differentiation, we first mapped the transcription start site of the mouse Dok-5 gene and characterized its promoter regions. Truncation and mutation analysis of the Dok-5 promoter identified the forkhead binding element responsible for the repression of Dok-5 promoter activation. The co-localization of FOXO3a and Dok-5 in the mouse heart allows FOXO3a to be a transcriptional regulator of Dok-5. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay confirmed that FOXO3a could bind to the Dok-5 promoter, accompanied by FOXO3a translocation from the nucleus to cytoplasm. FOXO3a overexpression could inhibit Dok-5 promoter activity. Silencing FOXO3a expression by siRNA upregulated the expression of Dok-5 and enhanced cardiomyocyte differentiation. Moreover, Dok-5 siRNA attenuated cardiomyocyte differentiation. Our results provide the first evidence that FOXO3a, the PI3K/PKB downstream substrate, acts as a transcriptional repressor to inhibit the expression of Dok-5. Dok-5 is involved in cardiomyocyte differentiation by a PI3K/PKB/FOXO3a signaling pathway.
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PMID:Dok-5 is involved in cardiomyocyte differentiation through PKB/FOXO3a pathway. 1980 Mar 50

The insulin receptor substrate (IRS) proteins are a family of cytoplasmic proteins that integrate and coordinate the transmission of signals from the extracellular to the intracellular environment via transmembrane receptors, thus regulating cell growth, metabolism, survival and proliferation. The PI3K/AKT/mTOR and MAPK signaling pathways are the best-characterized downstream signaling pathways activated by IRS signaling (canonical pathways). However, novel signaling axes involving IRS proteins (noncanonical pathways) have recently been identified in solid tumor and hematologic neoplasm models. Insulin receptor substrate-1 (IRS1) and insulin receptor substrate-2 (IRS2) are the best-characterized IRS proteins in hematologic-related processes. IRS2 binds to important cellular receptors involved in normal hematopoiesis (EPOR, MPL and IGF1R). Moreover, the identification of IRS1/ABL1 and IRS2/JAK2V617F interactions and their functional consequences has opened a new frontier for investigating the roles of the IRS protein family in malignant hematopoiesis. Insulin receptor substrate-4 (IRS4) is absent in normal hematopoietic tissues but may be expressed under abnormal conditions. Moreover, insulin receptor substrate-5 (DOK4) and insulin receptor substrate-6 (DOK5) are linked to lymphocyte regulation. An improved understanding of the signaling pathways mediated by IRS proteins in hematopoiesis-related processes, along with the increased development of agonists and antagonists of these signaling axes, may generate new therapeutic approaches for hematological diseases. The scope of this review is to recapitulate and review the evidence for the functions of IRS proteins in normal and malignant hematopoiesis.
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PMID:Insulin Substrate Receptor (IRS) proteins in normal and malignant hematopoiesis. 3032 53