Akt Protein Kinase Inhibits Rac1-GTP Binding through Phosphorylation at Serine 71 of Rac1

Kwon, Taegun; Kwon, Do Yoon; Chun, Jaesun; Kim, Jae Hong; Kang, Sang Sun

doi:10.1074/jbc.275.1.423

Cited by 207 publications

(191 citation statements)

References 52 publications

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“…Active Cdc42 has been shown to kill NGF-maintained sympathetic neurons and dominant-negative Cdc42 block death caused by NGF deprivation (Bazenet et al 1998). Interestingly the PI3 kinase effector Akt has been shown to phosphorylate and inactivate Rac in vitro (Kwon et al 2000). This observation is consistent with the observed increases in JNK signaling that are seen as a result of LY 294002-induced PI3 kinase inhibition (Tsui-Pierchala et al 2000).…”

Section: Mlks Are Key Activators Of Jnk In Neuronsmentioning

confidence: 54%

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Harris¹,

Maroney²,

Johnson

2002

Journal of Neurochemistry

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Cerebellar granule neurons grown in high potassium undergo rapid apoptosis when switched to medium containing 5 mM potassium, a stimulus mimicking deafferentation. This cell death can be blocked by genetic deletion of Bax, a member of the pro-apoptotic Bcl-2 family, cycloheximide an inhibitor of macromolecular synthesis or expression of dominant-negative c-jun. These observations suggest that Bax activation is the result of c-jun target gene(s) up-regulation following trophic withdrawal. Candidate genes include the BH3-only Bcl-2 family members Dp5 and Bim. The molecular mechanisms underlying granule cell neuronal apoptosis in response to low potassium were investigated using CEP-1347 (KT7515), an inhibitor of the MLK family of JNKKK. CEP-1347 provided protection of potassium-serum-deprived granule cells, but such neuroprotection was not long term. The incomplete protection was not due to incomplete blockade of the JNK signaling pathway because c-jun phosphorylation as well as induction of c-jun RNA and protein were completely blocked by CEP-1347. Following potassium-serum deprivation the JNKK MKK4 becomes phosphorylated, an event blocked by CEP-1347. Cells that die in the presence of CEP-1347 activate caspases; and dual inhibition of caspases and MLKs has additive, not synergistic, effects on survival. A lack of synergism was also seen with the p38 inhibitor SB203580, indicating that the neuroprotective effect of the JNK pathway inhibitor cannot be explained by p38 activation. Activation of the JNK signaling pathway seems to be a key event in granule cell apoptosis, but these neurons cannot survive long term in the absence of sustained PI3 kinase signaling. Neuronal survival is controlled in vivo by both retrograde signaling from neuronal targets as well as anterogradely via synaptic input. Cerebellar granule neurons are one such population whose survival is regulated by retrograde and anterograde signaling both in vivo and in vitro. In the lurcher mouse, cerebellar granule neurons die in response to the death of their targets, Purkinje neurons (Wetts and Herrup 1982). If the afferent activity to granule neurons is eliminated by mossy fiber axotomy, they undergo massive apoptosis (Borsello et al. 2000). These findings have been mimicked in vitro. Target-derived neurotrophic factors such as brain-derived growth factor (BDNF) and insulin-like growth factor (IGF)-1 promote the survival of cerebellar granule cells (Lindholm et al. 1993;Miller et al. 1997b). These neurons also undergo massive cell death when deafferentation is mimicked by removing the survival stimulus provided by depolarizing levels of potassium (Gallo et al. 1987). Abbreviations used: ASK, apoptosis signal regulating kinase 1; BAF, boc-aspartyl(OMe)-fluoromethylketone; BME, b-mercaptoethanol; CMV, cytomegalovirus; DEVD-amc, DEVD-aminomethylcoumarin; DIV, days in vitro; DTT, dithiothreitol; IP3, inositol-1,4,5-triphosphate; JNK, c-Jun N-terminal kinase; JNKKK, JNK kinase kinase; K5 ) S, buffer containing 5 mM KCl without serum; K25 + S, buf...

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Section: Mlks Are Key Activators Of Jnk In Neuronsmentioning

confidence: 54%

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Harris¹,

Maroney²,

Johnson

2002

Journal of Neurochemistry

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“…Serine 73 of RhoC GTPase lies within the switch II region between the effector protein-binding and GTP-binding domains (35,44). RhoC GTPase uniquely undergoes 2 conformational changes during its conversion from a GDPbound-signaling-inactive form to a GTP-bound-signalingactive form (44).…”

Section: Discussionmentioning

confidence: 99%

“…Studies suggest that Rho proteins can act as Akt substrates (35). Supplementary Table 2 is a comparison of putative Akt phosphorylation consensus sequences from known Akt effector proteins and Rac1, RhoC and RhoA GTPases.…”

Section: Phosphorylation Of Rhoc Gtpase In Ibc Cellsmentioning

confidence: 99%

Regulation of Inflammatory Breast Cancer Cell Invasion through Akt1/PKBα Phosphorylation of RhoC GTPase

Lehman

Laere

Golen

et al. 2012

Molecular Cancer Research

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With a 42% and 18% 5-and 10-year respective disease-free survival rate, inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer. IBC invades the dermal lymphatic vessels of the skin overlying the breast and as a consequence nearly all women have lymph node involvement and $1/3 have gross distant metastases at the time of diagnosis. One year after diagnosis $90% of patients have detectable metastases, making IBC a paradigm for lymphovascular invasion. Understanding the underlying mechanisms of the IBC metastatic phenotype is essential for new therapies. Work from our laboratory and others show distinct molecular differences between IBC and non-IBCs (nIBCs). Previously we showed that RhoC GTPase is a metastatic switch responsible for the invasive phenotype of IBC. In this study we integrate observations made in IBC patients with in vitro analysis. We show that the PI3K/Akt signaling pathway is crucial in IBC invasion. Key molecules involved in cytoskeletal control and cell motility are specifically upregulated in IBC patients compared with stage and cell-typeof-origin matched nIBCs patients. Distinctively, RhoC GTPase is a substrate for Akt1 and its phosphorylation is absolutely essential for IBC cell invasion. Further our data show that Akt3, not Akt1 has a role in IBC cell survival. Together our data show a unique and targetable pathway for IBC invasion and survival.

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“…First, Cdc42 activation was investigated in human metastatic prostate cancer PC-3 cells that were treated with the Cdc42 activator or 50 μM ZCL278 for 5, 10, and 15 min. Serine 71 phosphorylation is known to negatively regulate Rac/Cdc42 activity (22), and therefore an increase in phospho-Rac/Cdc42 expression is indicative of a decrease in active (i.e., GTP-bound) Rac/Cdc42. As depicted in Fig.…”

Section: Direct Binding Of Zcl278 and Cdc42 Demonstrated By Fluorescencementioning

confidence: 99%

Small molecule targeting Cdc42–intersectin interaction disrupts Golgi organization and suppresses cell motility

Friesland

Zhao

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

152

148

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Signaling through the Rho family of small GTPases has been intensely investigated for its crucial roles in a wide variety of human diseases. Although RhoA and Rac1 signaling pathways are frequently exploited with the aid of effective small molecule modulators, studies of the Cdc42 subclass have lagged because of a lack of such means. We have applied high-throughput in silico screening and identified compounds that are able to fit into the surface groove of Cdc42, which is critical for guanine nucleotide exchange factor binding. Based on the interaction between Cdc42 and intersectin (ITSN), a specific Cdc42 guanine nucleotide exchange factor, we discovered compounds that rendered ITSN-like interactions in the binding pocket. By using in vitro binding and imaging as well as biochemical and cell-based assays, we demonstrated that ZCL278 has emerged as a selective Cdc42 small molecule modulator that directly binds to Cdc42 and inhibits its functions. In Swiss 3T3 fibroblast cultures, ZCL278 abolished microspike formation and disrupted GM130-docked Golgi structures, two of the most prominent Cdc42-mediated subcellular events. ZCL278 reduces the perinuclear accumulation of active Cdc42 in contrast to NSC23766, a selective Rac inhibitor. ZCL278 suppresses Cdc42-mediated neuronal branching and growth cone dynamics as well as actin-based motility and migration in a metastatic prostate cancer cell line (i.e., PC-3) without disrupting cell viability. Thus, ZCL278 is a small molecule that specifically targets Cdc42–ITSN interaction and inhibits Cdc42-mediated cellular processes, thus providing a powerful tool for research of Cdc42 subclass of Rho GTPases in human pathogenesis, such as those of cancer and neurological disorders.

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Akt Protein Kinase Inhibits Rac1-GTP Binding through Phosphorylation at Serine 71 of Rac1

Cited by 207 publications

References 52 publications

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Identification of JNK‐dependent and ‐independent components of cerebellar granule neuron apoptosis

Regulation of Inflammatory Breast Cancer Cell Invasion through Akt1/PKBα Phosphorylation of RhoC GTPase

Small molecule targeting Cdc42–intersectin interaction disrupts Golgi organization and suppresses cell motility

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