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)

Individuals carrying a mutation in one of the three cerebral cavernous malformation genes (CCM1/KRIT1, CCM2, CCM3) cannot be clinically distinguished, raising the possibility that they act within common molecular pathways. In this study, we demonstrate that CCM3 (PDCD10) coprecipitates and colocalizes with CCM2. We also show that CCM3 directly binds to serine/threonine kinase 25 (STK25, YSK1, SOK1) and the phosphatase domain of Fas-associated phosphatase-1 (FAP-1, PTPN13, PTP-Bas, PTP-BL). CCM3 is phosphorylated by STK25 but not by its other Yeast-Two hybrid interactor STK24, whereas the C-terminal catalytic domain of FAP-1 dephosphorylates CCM3. Finally, our experiments reveal that STK25 forms a protein complex with CCM2. Thus, our data link two proteins of unknown function, CCM3 and STK25, with CCM2, which is part of signaling pathways essential for vascular development and CCM pathogenesis.
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PMID:CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations. 1765 16

Cerebral cavernous malformations (CCMs) may cause recurrent headaches, seizures, and hemorrhagic stroke and have been associated with loss-of-function mutations in CCM1/KRIT1, CCM2, and CCM3/programmed cell death 10 (PDCD10). The CCM3/PDCD10 amino acid sequence does not reveal significant homologies to protein domains with known structure. With the help of the only published human in-frame deletion of the CCM3 gene (c.97-?_150+?del), CCM3:p.L33_K50del, we have identified the interaction domain of CCM3 with the oxidant stress response serine/threonine kinase 25 (STK25, YSK1, SOK1) and with the mammalian Ste20-like kinase 4 (MST4, MASK). Consistently, nano-liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) analyses revealed two STK25 phosphorylation sites at serine 39 and threonine 43. The corresponding in-frame deletion of zebrafish ccm3a, dccm3:p.L31_K48del, also resulted in impaired interaction with STK25 and MST4. In agreement with the observed redundant biochemical functionality of zebrafish ccm3a and its duplicate ccm3b, simultaneous inactivation of both genes resulted in a progressive cardiovascular phenotype in zebrafish indistinguishable from ccm1 and ccm2 mutants. The pronounced cardiovascular dilatations could be recapitulated by morpholino-induced in-frame skipping of the exon encoding the STK25 and MST4 binding site of zebrafish Ccm3a if Ccm3b was repressed in parallel. Using a novel zebrafish model of CCM, we could thus demonstrate that the newly mapped STK25 and MST4 interaction domain within the CCM3 protein plays a crucial role for vascular development in zebrafish.
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PMID:Functional analyses of human and zebrafish 18-amino acid in-frame deletion pave the way for domain mapping of the cerebral cavernous malformation 3 protein. 1947 55

One of the CCM genes, CCM3/PDCD10, binds to the protein kinase family GCKIII, which comprises MST3/STK24, SOK1/STK25, and MST4/STK26. These proteins have been shown to have the same effect as CCM3, both in endothelial cells and in animal models such as zebrafish and are most likely involved in CCM pathogenesis. We describe here an in vitro kinase assay of GCKIII proteins which can be used to study their regulation in endothelial and other cells under different circumstances.
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PMID:Measuring the Kinase Activity of GCKIII Proteins In Vitro. 3252 71