The spatial resolution resulting from this strategy was instrumental for showing that spatial organization of RhoA activity existed and that compartmentation of signaling components may be a key regulatory feature in neuronal migration. Dick Hoekstra, in International Review of Cytology , Small GTPase rab proteins play an important role in various aspects of membrane traffic, including cargo selection, vesicle budding, vesicle motility, tethering, docking, and fusion.
Recent data suggest also that rabs, and their divalent effector proteins, organize organelle subdomains and as such may define functional organelle identity. Most rabs are ubiquitously expressed.
This review discusses the role of rabs in epithelial membrane transport. These proteins are considered molecular switches that determine the temporal aspects of a broad variety of signaling events involved in numerous cellular processes and responses.
Cytoskeleton and Small G Proteins
The G domain responsible for guanine nucleotide binding is highly conserved between the different families of GTPases. Some families are maintained inactive through binding guanosine nucleotide dissociation inhibitors GDIs. These accessory proteins not only prevent nucleotide exchange but also restrict relocalization of GTPases to membranes. Loading of guanosine triphosphate GTP results in the stabilization of a new 3D conformation that enables them to interact with and modulate the activity of different and specific effector proteins. Some GTPases possess limited intrinsic GTPase activity, which depends on a few conserved amino acids in critical positions.
More than small G proteins have been identified in humans.
These are traditionally classified into five families. Ras proteins were the first members of the entire superfamily and were initially discovered on the basis of their homology to rat sarcoma virus genes. The best-characterized members are H-Ras, N-Ras, and K-Ras, which have been implicated in many types of cancers and considered protooncogenes.
However, the Ral and Rap families of small GTPases also belong to this prototypical class of more than 30 members. Members of the Ras homologous Rho family comprise a second group of more than 20 proteins. This family of GTPase is well known for its role in remodeling of the actin cytoskeleton and gene expression.
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The third family, the Rabs, includes more than 60 isoforms. Their main function in cells is to finely tune many steps of vesicle trafficking vesicle formation, vesicle movement, and membrane fusion. The fourth family is the ADP-ribosylation factors ARFs , which also regulate vesicle budding through regulation of coat polymerization and disassembly. Some ARF isoforms are also involved in actin rearrangement and lipid remodeling.
The last family of GTPases consists of only one member, Ran Ras-related Nuclear protein , which regulates nucleoplasmic transport during interphase. This small G protein controls cell cycle progression. Small GTPases are critical regulators of cytoskeletal and membrane dynamics underlying cell motility, cell polarity, and cell growth. Not surprisingly, both Ras- and Rho-family small GTPases have been involved in axon specification and axon growth.
Ras proteins regulate both the MAP kinase and PI3K pathways, and pharmacologic inhibition of either pathway was sufficient to inhibit the production of additional axons, but surprisingly it did not impact axon formation in general Yoshimura et al. Ras activation is coupled to many cell surface receptors including growth factor receptors, and a EGFR tyrosine kinase inhibitor, AG, can inhibit axon formation Shi et al.
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Elegant work using a fluorescent reporter of Ras activation demonstrates the restricted nature of Ras signaling and its recruitment during axon determination to contribute to a positive feedback loop with PI3K Fivaz et al. Additional work remains to identify which upstream activators may regulate Ras during neuronal symmetry breaking to determine the nascent axon; we discuss some potential candidates later in this chapter.
Expression of dominant-negative locked in GDP-bound state or constitutively active locked in GTP-bound state mutants of each of these small GTPases in polarizing neurons, or treatment with the Rho-GTPase inhibitor toxin B Bradke and Dotti, , indicates a critical role for both cdc42 and Rac1 both in vitro in rodent neurons Nishimura et al.
Specifically, the expression of Cdc42 L28 , a cdc42 mutation that constitutively cycles between a GDP- and GTP-bound state, leads to the formation of multiple axons in rodent neurons. The loss of cdc42 expression, either through siRNA knockdown Schwamborn and Puschel, or genetic ablation Garvalov et al. In the case of cdc42 conditional knockout mice, the axon phenotype may be due to increased levels of phosphorylated inactive cofilin, a regulator of actin dynamics enriched in developing axons Garvalov et al.
Paradoxically, Pak1 activity is greatly reduced in cdcnull mice, suggesting that the deregulation of another pathway regulating cofilin occurs in the absence of cdc42, most likely the RhoA-regulated kinase ROCK Maekawa et al. The loss of Pak1 itself also inhibits neuronal polarization, and conversely, constitutively active Pak1 induces multiple tau1-positive processes Jacobs et al. The latter effect can be partially reduced by coexpression of either an unphosphorylatable form of cofilin or a GDP-locked Rac1, suggesting that Rac1 may act downstream of Pak1 activation.
RhoA is another small GTPase , and it is typically associated with destabilization of the actin cytoskeleton and myosin-based contractility. Experiments using a constitutively active form of RhoA show that it inhibits neuritogenesis, whereas a dominant-negative form of RhoA enhances neurite outgrowth Schwamborn and Puschel, The examination of Rac1's role in neuronal polarization has led to some confounding results.
Cytoskeleton and Small G Proteins - : MANZ
In cultured neurons, a constitutively active version of Rac1 does not affect axon specification Schwamborn and Puschel, These results, while mixed, do hint at a more complex regulation of Rac1 in neuronal polarization. This fact becomes clearer later in this review because the only GEF proteins shown to be crucial for axon formation appear to control Rac1.
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This observation's apparent disjunction with the lack of strong phenotype may reflect the importance of subcellular localization of activated pools of Rac1 and compensation by related small GTPases. Small GTPases have a plethora of effectors within cells, and proper activation of these effectors, both spatially and temporally, requires exquisite control of both activation and inactivation by GEFs and GAPs, respectively.
Another axonally enriched, unconventional Rac1 regulatory protein is the cytoplasmic dynein light chain TcTEX-1 Chuang et al. Multiple axons result from overexpression, and this effect is preserved using a mutant form T94E that cannot bind dynein heavy chain. Consistent with a role in controlling Rac1, the supranumerary axon phenotype is suppressed by constitutively active RhoA or dominant negative Rac1.
Rap1b, a member of the Ras superfamily of GTPases, is also required for proper neuronal polarization in vitro Schwamborn and Puschel, ; Schwamborn et al. It is found at the tip of the nascent axon, and its overexpression leads to hippocampal neurons bearing multiple axons.
Cytoskeleton and Small G Proteins
The loss of Rap1b following siRNA knockdown abrogates axon formation, and expression of autocycling cdc42 can rescue the phenotype. Expression of a constitutively active Rap1b fails to reverse the loss of axons observed following a loss of cdc42, indicating that Rap1b lies upstream of cdc42 in this pathway of neuron polarization.
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