Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Within epithelial tissue, cells are held together by specialized lateral junctions. At particular stages of development and in pathological processes such as metastasis, cells break down the intercellular junctions, separate from the epithelial sheet and migrate individually. Despite the importance of these processes, little is understood about the regulatory mechanisms of active cell separation. In view of the effects of insulin-like growth factor I (IGF-I) on mammary gland development and cancer, we developed a model using MCF-7 human breast cancer cells in which the process of cell separation can be induced by IGF-I. The separation was enhanced in MCF-7 cells overexpressing the IGF-IR and blocked in the cells expressing a dead-kinase mutant of this receptor. Activation of the IGF-IR resulted in a rapid formation of motile actin microspikes at the regions of cell-cell contacts, disorganization of mature adherens junctions and the onset of cell migration. In cell separation, the signaling between the IGF-IR kinase and actin required phosphatidylinositol 3 (PI 3)-kinase-generated phospholipids but not MAP kinases and was mediated by alpha-actinin. The activity of MEK1/2 kinases was needed for consecutive cell migration. This work also defined a new function for alpha-actinin. Upon IGF-IR activation, green fluorescence protein (GFP)-labeled alpha-actinin concentrated at the base of actin microspikes. Deletion of the N-terminal actin-binding domain of alpha-actinin prevented this redistribution, indicating that this domain is necessary. Detection of the C-terminal tail of alpha-actinin reduced the number of microspikes, showing that alpha-actinin has a role in the development of microspikes and is not passively reorganized with filamentous actin. We suggest that the signaling pathway from the IGF-IR kinase through the PI-3 kinase to alpha-actinin participates in the rapid organization of actin into microspikes at the cell-cell junctions and leads to active cell separation, whereas signaling through ERK1/2 MAP kinases controls cell migration following cell separation.
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PMID:Functional role of alpha-actinin, PI 3-kinase and MEK1/2 in insulin-like growth factor I receptor kinase regulated motility of human breast carcinoma cells. 1235 18

Endothelial cells respond to mechanical stresses of the circulation with cytoskeletal rearrangements such as F-actin stress fiber alignment along the axis of fluid flow. Endothelial cells are exposed to hypertonic stress in the renal medulla or during mannitol treatment of cerebral edema. We report here that arterial endothelial cells exposed to hypertonic stress rearranged F-actin into novel actin-myosin II fibers with regular 0.5-microm striations, in which alpha-actinin colocalizes with actin. These striated fibers assembled over hours into three-dimensional, irregular, polygonal actin networks most prominent at the cell base, and occasionally surrounding the nucleus in a geodesic-like structure. Hypertonicity-induced assembly of striated polygonal actin networks was inhibited by cytochalasin D, blebbistatin, cell ATP depletion, and intracellular Ca(2+) chelation but did not require intact microtubules, regulatory volume increase, or de novo RNA or protein synthesis. Striated polygonal actin network assembly was insensitive to inhibitors of MAP kinases, tyrosine kinases, or phosphatidylinositol 3-kinase, but was prevented by C3 exotoxin, by the RhoA kinase inhibitor Y-27632, and by overexpressed dominant-negative RhoA. In contrast, overexpression of dominant-negative Rac or of dominant-negative cdc42 cDNAs did not prevent striated polygonal actin network assembly. The actin networks described here are novel in structure, as striated actin-myosin structures in nonmuscle cells, as a cellular response to hypertonicity, and as a cytoskeletal regulatory function of RhoA. Endothelial cells may use RhoA-dependent striated polygonal actin networks, possibly in concert with cytoskeletal load-bearing elements, as a contractile, tension-generating component of their defense against isotropic compressive forces.
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PMID:Hypertonicity triggers RhoA-dependent assembly of myosin-containing striated polygonal actin networks in endothelial cells. 1719 81

The p38 MAP kinases are stress-activated MAP kinases whose induction is often associated with the onset of heart failure. This study investigated the role of p38 MAP kinase isoforms in the regulation of myocardial contractility and ischemia/reperfusion injury using mice with cardiac-specific expression of kinase dead (dominant negative) mutants of p38alpha (p38alphadn) or p38beta (p38betadn). Hearts were subjected to 20 min ischemia and 40 min reperfusion. Immunofluorescence staining for p38alphadn and p38betadn protein was performed on neonatal cardiomyocytes infected with adenovirus expressing flag-tagged p38alphadn and p38betadn protein. Basal contractile function was increased in both p38alphadn and p38betadn hearts compared to WT. Ischemic injury was increased in p38betadn vs. WT hearts, as indicated by lower posti-schemic recoveries of contractile function and ATP. However, despite a similar increase in contractility, ischemic injury was not increased in p38alphadn vs. WT hearts. Immunohistological analysis of cardiomyocytes with comparable levels of protein overexpression show that p38alphadn and p38betadn proteins were co-localized with sarcomeric alpha-actinin, however, p38alphadn was detected in the nucleus while p38betadn was exclusively detected in the cytosol. In summary, attenuated p38 activity led to increased myocardial contractility; specific isoforms of p38 and their sub-cellular localization may have different roles in modulating ischemic injury.
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PMID:Effect of p38 MAP kinases on contractility and ischemic injury in intact heart. 1970 73