P-Rex1 is required for efficient melanoblast migration and melanoma metastasis

Lindsay, Colin R.; Lawn, Samuel; Campbell, Andrew D.; Faller, William J.; Rambow, Florian; Mort, Richard L.; Timpson, Paul; Li, Ang; Cammareri, Patrizia; Ridgway, Rachel A.; Morton, Jennifer P.; Doyle, Brendan; Hegarty, Shauna; Rafferty, Máirín; Murphy, Ian; McDermott, Enda; Sheahan, Kieran; Pedone, Katherine H.; Finn, Alexander J.; Groben, Pamela A.; Thomas, Nancy E.; Hao, Honglin; Carson, Craig C.; Norman, Jim C.; Machesky, Laura M.; Gallagher, William M.; Jackson, Ian J.; Kempen, Léon C van; Beermann, Friedrich; Der, Channing J.; Larue, Lionel; Welch, Heidi; Ozanne, Brad; Sansom, Owen J.

doi:10.1038/ncomms1560

Cited by 162 publications

(226 citation statements)

References 38 publications

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“…The Prex1 −/− mice in the C57BL6 background were a kind gift from Heidi Welch, The Babraham Institute, Cambridge, UK (10). Generation of this knockout line was described previously (9).…”

Section: Methodsmentioning

confidence: 99%

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Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Chai

Wang

et al. 2015

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

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Autism spectrum disorders (ASDs) are a group of highly inheritable mental disorders associated with synaptic dysfunction, but the underlying cellular and molecular mechanisms remain to be clarified. Here we report that autism in Chinese Han population is associated with genetic variations and copy number deletion of P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1). Genetic deletion or knockdown of P-Rex1 in the CA1 region of the hippocampus in mice resulted in autism-like social behavior that was specifically linked to the defect of long-term depression (LTD) in the CA1 region through alteration of AMPA receptor endocytosis mediated by the postsynaptic PP1α (protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling pathway. Rescue of the LTD in the CA1 region markedly alleviated autism-like social behavior. Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs. Several studies have documented impairments of social recognition [e.g., such as deficits in recognizing unfamiliar faces (2)] and in behavioral flexibility [e.g., impaired reversal learning and difficulties in error correction (3, 4)] in autistic people. However, the neurobiological mechanism responsible for the symptoms of ASDs, and especially for the deficit in social recognition, is little known.Recent genetic studies have identified a large number of candidate genes for ASDs (5, 6), including many that code for synaptic proteins. Synaptic dysfunction may play a critical role in ASDs (7).Here we have identified a new autism-associated gene, Prex1, that codes for P-Rex1 (phosphatidylinositol-3,4,5-trisphosphatedependent Rac exchange factor 1), a Rac-specific Rho GTPase guanine nucleotide exchange factor (GEF). This gene is known to be highly expressed in neutrophils and in the mouse brain (8). Mice with the Prex1 gene deleted (Prex1 −/− ) exhibited Racdependent mild neutrophilia (9) and melanoblast migration defects (10). P-Rex1 influences neuronal cell motility (11) and neurite elongation (12) by regulating actin dynamics specifically at the growth cone. However, the role of P-Rex1 in regulating synaptic function and related behaviors remains unknown.In addition to identifying an association between PREX1 and autism in humans, we demonstrate that genetic disruption of P-Rex1 in mice leads to autism-like social behavior and to other features known to be associated with ASDs. Electrophysiological studies revealed a specific impairment of NMDA receptor (NMDAR)-dependent long-term depression (LTD) at Schaffer collateralcornus ammonis region 1 (SC-CA1) synapses. Furthermore, these defects were associated with dysfunction in NMDA-induced AMPA receptor (AMPAR) endocytosis, because of defective PP1α (serine/threonine protein phosphase 1α)-P-Rex1-Rac1 (Ras-related C3 botulinum toxin substrate 1) signaling, and correcting the latter rectified the social recognition defici...

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Section: Methodsmentioning

confidence: 99%

“…This gene is known to be highly expressed in neutrophils and in the mouse brain (8). Mice with the Prex1 gene deleted (Prex1 −/− ) exhibited Racdependent mild neutrophilia (9) and melanoblast migration defects (10). P-Rex1 influences neuronal cell motility (11) and neurite elongation (12) by regulating actin dynamics specifically at the growth cone.…”

mentioning

confidence: 99%

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Chai

Wang

et al. 2015

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

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“…In human cancers, persistent RhoGEF activation or loss of RhoGAP stimulation are common mechanisms leading to aberrant Rho activation. For example, we determined that the P-Rex1 RhoGEF was up-regulated transcriptionally in melanoma through persistent activation of the ERK mitogen-activated protein kinase pathway and the related P-Rex2 isoform was found mutationally activated in melanoma (9,10).…”

Section: Stard12mentioning

confidence: 99%

CRL4A-FBXW5–mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth

Kim

Jackson

Xiong

et al. 2013

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

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DLC1 encodes a RhoA GTPase-activating protein and tumor suppressor lost in cancer by genomic deletion or epigenetic silencing and loss of DLC1 gene transcription. We unexpectedly identified nonsmall cell lung cancer (NSCLC) cell lines and tumor tissue that expressed DLC1 mRNA yet lacked DLC1 protein expression. We determined that DLC1 was ubiquitinated and degraded by cullin 4A-RING ubiquitin ligase (CRL4A) complex interaction with DDB1 and the FBXW5 substrate receptor. siRNA-mediated suppression of cullin 4A, DDB1, or FBXW5 expression restored DLC1 protein expression in NSCLC cell lines. FBXW5 suppression-induced DLC1 reexpression was associated with a reduction in the levels of activated RhoA-GTP and in RhoA effector signaling. Finally, FBXW5 suppression caused a DLC1-dependent decrease in NSCLC anchorage-dependent and -independent proliferation. In summary, we identify a posttranslational mechanism for loss of DLC1 and a linkage between CRL4A-FBXW5-associated oncogenesis and regulation of RhoA signaling.Rho-selective GTPase-activating protein | Rho GTPase-activating protein 7 | STARD12 R ho family small GTPases function as extracellular signalregulated on-off switches that cycle between an active GTPbound state and an inactive GDP-bound state. Of the 20 human Rho family GTPases, the best studied are RhoA, Rac1, and Cdc42 (1). Rho-selective guanine nucleotide exchange factors (RhoGEFs) promote GDP-GTP exchange and formation of active Rho-GTP, whereas Rho-selective GTPase-activating proteins (RhoGAPs) stimulate hydrolysis of the bound GTP to return the GTPase to its inactive Rho-GDP form (2, 3). Rho-GTP binds preferentially to its downstream effectors, stimulating a diversity of cytoplasmic signaling cascades that control actin organization, cell morphology and polarity, cell cycle progression and cell proliferation, cell survival and migration, and gene expression (4).In light of their key role in regulating fundamental processes in cell behavior, it is not surprising that the aberrant activation of Rho family small GTPases contributes to cancer and other human disorders (5-8). However, in contrast to the Ras small GTPase, where direct mutational activation leads to insensitivity to inactivation by Ras-selective GTPase-activating proteins (RasGAPs), Rho GTPases are more commonly activated through indirect mechanisms (2, 3). In human cancers, persistent RhoGEF activation or loss of RhoGAP stimulation are common mechanisms leading to aberrant Rho activation. For example, we determined that the P-Rex1 RhoGEF was up-regulated transcriptionally in melanoma through persistent activation of the ERK mitogen-activated protein kinase pathway and the related P-Rex2 isoform was found mutationally activated in melanoma (9, 10).With regard to RhoGAPs, one of the most frequent and common mechanisms involves loss of expression of Deleted in Liver Cancer 1 (DLC1) in liver, breast, lung, ovarian, kidney, colon, stomach, prostate, and other cancers (3,11,12). DLC1 encodes a GAP primarily for RhoA and related isoforms. Initially ...

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“…Additionally, PREX1 appears to have a specific role in metastasis. The expression of PREX1, but not a GEF-dead mutant, induces spontaneous metastasis in a xenograft prostate cancer mouse model (24), and PREX1 inactivation in mice reduces metastasis in a melanoma transgenic mouse model (23). PREX2 is also overexpressed in numerous cancer types and is frequently mutated in cancer, with especially high mutation rates in melanoma (25)(26)(27).…”

mentioning

confidence: 99%

“…PREX1 is overexpressed in a variety of human cancers, including melanoma and breast, prostate, and colon cancer (17,(23)(24)(25)(26). PREX1 knockdown decreases tumor growth in xenograft mouse models of cancer using breast cancer cell lines (17,18).…”

mentioning

confidence: 99%

PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

Barrows

Parsons

2016

Journal of Biological Chemistry

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P-Rex1 is required for efficient melanoblast migration and melanoma metastasis

Cited by 162 publications

References 38 publications

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior

CRL4A-FBXW5–mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth

PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

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