Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We review here signalling complexes that we have defined using X-ray analysis in our laboratory. They include growth factors and their receptors: nerve growth factor (NGF) and its hetero-hexameric 7S NGF storage complex, hepatocyte growth factor/scatter factor (HGF/SF) NK1 dimers and fibroblast growth factor (FGF1) in complex with its receptor (FGFR2) ectodomain and heparin. We also review our recent structural studies on intracellular signalling complexes, focusing on phosducin transducin GPry, CK2 protein kinase and its complexes, and the cyclin D-dependent kinase, Cdk6, bound to the cell cycle inhibitor p19INK4d. Comparing the structures of these complexes with others we show that the surface area buried in signalling interactions does not always give a good indication of the strength of the interactions. We show that conformational changes are often important in complexes with intermediate buried surface areas of 1500 to 2000 A2, such as Cdk6INK4 interactions. Some interactions involve recognition of continuous epitopes, where there is no necessity for a tertiary structure and very often the binding conformation is induced during the process of interaction, for example phosducin binding to the betagamma subunits (Gtbetagamma) of the heterotrimeric G protein transducin.
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PMID:Protein-protein interactions in receptor activation and intracellular signalling. 1107 27

We have previously cloned the alternatively spliced isoform of fibroblast growth factor receptor 3 (FGFR3DeltaAB) that lacks the acid box in the extracellular region. To understand the biological functions and signal transduction of these FGFR3 isoforms, we analyzed the effect of FGF1 in ATDC5 cells, chondroprogenitor cell lines overexpressing these isoforms. In response to FGF1, FGFR3 induced a marked cell-morphology change to a round shape, while FGFR3DeltaAB did not. Furthermore, FGFR3 induced complete growth arrest, whereas FGFR3DeltaAB induced only moderate growth inhibition. Both receptors induced the expression of the CDK inhibitor p21(CIP1). However, only FGFR3 induced STAT1 phosphorylation that mediates the transcriptional induction of p21(CIP1), although both FGFR3 isoforms could induce a strong activation of mitogen-activated protein (MAP) kinases. Taken together, the different biological responses mediated by FGFR3 and FGFR3DeltaAB appear to be due to a difference in their ability to utilize STAT1 pathway and signals involved in cell rounding.
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PMID:FGFR3 isoforms have distinct functions in the regulation of growth and cell morphology. 1177 41

Since little is known about the function of polypeptide growth factors as regulators of multiple cell cycles, we compared the ability of FGF1, PDGF-AB and serum to induce a second round of DNA synthesis in Swiss 3T3 cells previously exposed to either FGF1, PDGF-AB or serum during the first cell cycle using [14C]- and [3H]thymidine in a double labeling system to distinguish between the first and second cell cycles. Surprisingly, we observed that cells exposed to either FGF1 or PDGF-AB in the first cell cycle were unable to synthesize DNA in response to FGF1 or PDGF-AB in the second cell cycle; yet these cells responded well to serum as a second cycle mitogen. Interestingly, while cells exposed to either FGF1 or PDGF-AB in the second cycle displayed normal receptor-mediated signaling and expressed cyclin D and E, they, like senescent fibroblasts and endothelial cells, failed to express cyclin A, and the continuous exposure of cells to either FGF1 or PDGF-AB resulted in a decrease in the kinase activity of the cyclin E/cdk2 complex. In addition, an increased association of this complex was observed with p21 CIP in an FGF1-dependent manner as well as with p27 KIP in a PDGF-AB-dependent manner. Lastly, the downregulation of p21 expression using an antisense strategy was able to partially rescue the replicative response of Swiss 3T3 cells to FGF1 in the second cycle. These data suggest that (i) FGF1 and PDGF-AB may limit their mitogenic effect to a single cell cycle, (ii) entry into the second round of replication is serum dependent and (iii) the self-limiting nature of FGF1 and PDGF-AB correlates with the accumulation of the cdk inhibitors, p21 and p27, respectively.
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PMID:Stimulation of quiescent cells by individual polypeptide growth factors is limited to one cell cycle. 1550 56