Elongation factor-1α stabilizes microtubules in a calcium/calmodulin-dependent manner

Moore, Richard C.; Durso, Neil A.; Cyr, Richard J.

doi:10.1002/(sici)1097-0169(1998)41:2<168::aid-cm7>3.0.co;2-a

Cited by 76 publications

(37 citation statements)

References 56 publications

(82 reference statements)

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“…This may provide a mechanism by which muscarinic activation can increase dendritic translation and may also allow for muscarinic regulation of other functions of eEF1A2. eEF1A has been demonstrated to bind and bundle actin (49), bind microtubules (50,51), bind calmodulin (52), and regulate apoptosis (53). Also, this interaction may provide a molecular mechanism underlying functional differences between the two closely related mAChR subtypes, M 2 and M 4 .…”

Section: Discussionmentioning

confidence: 99%

Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2

McClatchy¹,

Knudsen²,

Clark³

et al. 2002

Journal of Biological Chemistry

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The activation of the muscarinic acetylcholine receptor (mAChR) family, consisting of five subtypes (M 1 -M 5 ), produces a variety of physiological effects throughout the central nervous system. However, the role of each individual subtype remains poorly understood. To further elucidate signal transduction pathways for specific subtypes, we used the most divergent portion of the subtypes, the intracellular third (i3) loop, as bait to identify interacting proteins. Using a brain pull-down assay, we identify elongation factor 1A2 (eEF1A2) as a specific binding partner to the i3 loop of M 4 , and not to M 1 or M 2 .In addition, we demonstrate a direct interaction between these proteins. In the rat striatum, the M 4 mAChR colocalizes with eEF1A2 in the soma and neuropil. In PC12 cells, endogenous eEF1A2 co-immunoprecipitates with the endogenous M 4 mAChR, but not with the endogenous M 1 mAChR. In our in vitro model, M 4 dramatically accelerates nucleotide exchange of eEF1A2, a GTP-binding protein. This indicates the M 4 mAChR is a guanine exchange factor for eEF1A2. eEF1A2 is an essential GTP-binding protein for protein synthesis. Thus, our data suggest a novel role for M 4 in the regulation of protein synthesis through its interaction with eEF1A2.In the central nervous system, the muscarinic acetylcholine receptors (mAChR) 1 play crucial roles in learning, memory, movement, analgesia, and sleep (1-3). Dysfunction in mAChR signaling has been implicated in brain disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia (4 -6). The mAChRs belong to the G-protein-coupled receptor (GPCR) superfamily. Upon agonist binding, GPCRs bind and activate heterotrimeric G-proteins, which in turn activate various downstream targets. There are two distinct, well characterized G-protein signaling pathways activated by the five mAChR subtypes. M 1 , M 3 , and M 5 couple to G q , which stimulates phospholipase C-␤, and thus releases calcium from intracellular stores and activates protein kinase C (7, 8). M 2 and M 4 are coupled to G i/o , which regulates adenylate cyclase (9). These subtypes are expressed throughout the brain, and, in some brain regions, multiple subtypes are expressed in individual neurons (10). The diversity of physiological effects and the overlapping expression pattern of the muscarinic receptor subtypes suggest that there are signaling pathways initiated by the mAChRs independent of these two heterotrimeric G-protein pathways.Signaling pathways independent of heterotrimeric G-proteins have been reported throughout the GPCR superfamily (11-14). Evidence supporting this hypothesis stems from the identification of novel binding partners of GPCRs other than the traditional heterotrimeric G-proteins. Within the muscarinic family in particular, there is an especially large body of evidence to suggest the existence of nontraditional signaling pathways. There are many reports of G-protein-independent regulation of ion channels by mAChRs (15-18). Moreover, the M 3 mAChR has been found to associate ...

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Section: Discussionmentioning

confidence: 99%

Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2

McClatchy¹,

Knudsen²,

Clark³

et al. 2002

Journal of Biological Chemistry

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“…We also found that SIAH interacts, in the two-hybrid assay, with the elongation factor 1a (EF-1a) (data not shown). EF-1a named for its role in protein translation, is a highly conserved ubiquitous GTP-binding protein that bundles and severes microtubules by interacting with the C-terminus of tubulin (Condeelis, 1995); (Moore et al, 1998;Shiina et al, 1994). SIAH e ect on Kid and EF1a could eventually be paralleled.…”

Section: Discussionmentioning

confidence: 99%

SIAH-1 interacts with α-tubulin and degrades the kinesin Kid by the proteasome pathway during mitosis

et al. 2000

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SIAH-1, a human homologue of the Drosophila seven in absentia (Sina), has been implicated in ubiquitinmediated proteolysis of di erent target proteins through its N-terminal RING ®nger domain. SIAH-1 is also induced during p53-mediated apoptosis. Furthermore, SIAH-1-transfected breast cancer cell line MCF-7 exhibits an altered mitotic process resulting in multinucleated giant cells. Now, using the two-hybrid system, we identi®ed two new SIAH interacting proteins: Kid (kinesin like DNA binding protein) and a-tubulin. We demonstrate that SIAH is involved in the degradation of Kid via the ubiquitin ± proteasome pathway. Our results suggest that SIAH-1 but not its N-terminal deletion mutant, a ects the mitosis by an enhanced reduction of kinesin levels. Our results imply, for the ®rst time, SIAH-1 in regulating the degradation of proteins directly implicated in the mitotic process. Oncogene (2000) 19, 5997 ± 6006.

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“…Genes associated with transcription were downregulated, including GKLF and an inhibitor of DNA binding 2. EEF1A1 was downregulated; this gene modulates the dynamic behavior of microtubules assembled from tubulin sources and regulates the cell cycle (Moore et al, 1998). In parallel with the down- Differentiation genes altered in esophageal cancer A Luo et al regulation of EEF1A1, the chaperone, heat shock protein 70, was also downregulated.…”

Section: Alterations Of Gene Expression In Esccmentioning

confidence: 97%

Discovery of Ca2+-relevant and differentiation-associated genes downregulated in esophageal squamous cell carcinoma using cDNA microarray

et al. 2003

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Elongation factor-1α stabilizes microtubules in a calcium/calmodulin-dependent manner

Cited by 76 publications

References 56 publications

Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2

Novel Interaction between the M4 Muscarinic Acetylcholine Receptor and Elongation Factor 1A2

SIAH-1 interacts with α-tubulin and degrades the kinesin Kid by the proteasome pathway during mitosis

Discovery of Ca2+-relevant and differentiation-associated genes downregulated in esophageal squamous cell carcinoma using cDNA microarray

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