Written in English
Many different aspects of cellular behavior, function, and morphology are regulated by signaling pathways that are able to translate numerous types of extracellular stimuli into tremendously diverse types of responses. Surprisingly, the cell uses many of the same signaling proteins in different signal transduction cascades. Thus one outstanding biological question is how are specific responses achieved if the same signaling proteins are activated in a variety of contexts? An excellent example of the ability of particular signaling proteins and pathways to regulate different responses is signaling involving the Rho family of small GTPases. Rho GTPases are activated by the exchange of bound GDP to GTP, which results in a conformational change in the protein and the activation of downstream signaling pathways. First characterized as regulators of the actin cytoskeleton, Rho GTPases have now also been implicated in the regulation of other cytoskeletal components, transcription, translation, cell-cycle progression, and vesicular trafficking. However it is not understood how a specific outcome, amongst many possible outcomes, arises following activation of Rho GTPase family by a particular stimuli.Here I describe a role for the Rho GTP Exchange Factor (RhoGEF) Lfc in regulating microtubule stability and organization during interphase and mitosis by specifying the outcome of Rho GTPase activation. I show that Lfc signaling promotes microtubule stability in a Rho-dependent manner, and that inhibition of Lfc and Rho signaling during early mitosis results in defects in spindle assembly. I demonstrate that Lfc is recruited to microtubules and the mitotic spindle via associations with the dynein-dynactin complex. Furthermore I show that the activation of Lfc, and in turn Rho GTPase, is tightly regulated by protein-protein interactions with dynein-dynactin. I propose that all RhoGEFs likely act not only to regulate the spatial and temporal activation of Rho GTPases by recruiting Rho signaling to particular signaling complexes, but in doing so also act to specify the outcome of Rho activation.
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Guanine nucleotide-exchange factors (GEFs) are directly responsible for the activation of Rho-family GTPases in response to diverse extracellular . The microtubule-associated guanine nucleotide exchange factor (GEF)-H1 activates RhoA when released from microtubules to initiate a RhoA/Rho kinase/myosin light chain signaling pathway that regulates cellular contractility. However, the contributions of activated GEF-H1 to coordination of cytoskeletal dynamics during cell migration are unknown. GEF-H1/Lfc is a guanine nucleotide exchange factor for RhoA (Benais-Pont et al., ; Aijaz et al., ; Birkenfeld et al., ). In contrast to permanent cell lines, GEF-H1 is expressed at very low levels in primary cultures of differentiated RPE cells (Figure 1 G), similar to the levels previously reported for adult epithelial tissues. Glaven JA, Whitehead IP, Nomanbhoy T, Kay R, Cerione RA () Lfc and Lsc oncoproteins represent two new guanine nucleotide exchange factors for the Rho GTP-binding protein. J Biol Chem – PubMed CrossRef Google ScholarCited by:
Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function Cited by: Cloning and characterization of GEF-H1, a microtubule-associated guanine nucleotide exchange factor for Rac and Rho GTPases. J Biol Chem , Author: Christina H. Eng, Gregg G. Gundersen. Neuronal migration is essential for the orchestration of brain development and involves several contiguous steps: interkinetic nuclear movement (INM), multipolar–bipolar transition, locomotion, and translocation. Growing evidence suggests that Rho GTPases, including RhoA, Rac, Cdc42, and the atypical Rnd members, play critical roles in neuronal migration by regulating both actin Cited by: 3. Brain-derived neurotrophic factor. DAG. Diacylglycerol. DSM-IV. Diagnostic and statistical manual of mental disorders, fourth edition. GAP. GTPase-activating protein. GDI. Guanine nucleotide dissociation inhibitor. GEF. Guanine nucleotide exchange factor. GTPase. Guanosine-5′-triphosphatase. GWAS. Genome-wide association study. JNK. c-Jun-N Author: María J. Caloca, Laura Barrio-Real, Rogelio González-Sarmiento.
PSD associates with and promotes synaptic localization of kalirin-7, a guanine nucleotide exchange factor (GEF) for Rac1. Shank binds β PIX, a GEF for Rac1 and Cdc42, and promotes synaptic localization of β PIX and β PIX-associated PAK, a kinase downstream of Rac1 and Cdc42 that regulates spine morphogenesis through LIMK-1 and MLC. Bakal CJ, Finan D, LaRose J, Wells CD, Gish G, Kulkarni S, DeSepulveda P, Wilde A, Rottapel R () The Rho GTP exchange factor Lfc promotes spindle assembly in early mitosis. Proc Natl Acad Sci U S A , – Cited by: 6. Ren Y, Li R, Zheng Y, Busch H () Cloning and characterization of GEF-H1, a microtubule-associated guanine nucleotide exchange factor for Rac and Rho GTPases. J Biol Chem – [Google Scholar]. An underlying premise of the book is that understanding of their shared pathogenic mechanisms will lead to improved therapies. Given the rapid evolution of the field of Neuroimmune Pharmacology, readers will find this book to be the most timely and authoritative reference on the subject of each of its chapters.