Arhgap36-dependent activation of Gli transcription factors

Rack, Philip D.; Ni, Jun; Payumo, Alexander Y.; Nguyen, Vien; Crapster, J. Aaron; Hovestadt, Volker; Kool, Marcel; Jones, David; Mich, John K.; Firestone, Ari J.; Pfister, Stefan M.; Cho, Yoon Jae; Chen, James

doi:10.1073/pnas.1322362111

Cited by 39 publications

(73 citation statements)

References 47 publications

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“…ARHGAP36 is poorly investigated. It has been shown to be involved in Gli transcription factor activation but independent on its GAP domain (98). The ARFGAP and RHOGAP domain-containing CNT-D1 (also called ARAP2; Table 1) lacks RHOGAP activity and acts as an ARF6 GAP (99).…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins

Amin

Jaiswal

Derewenda

et al. 2016

Journal of Biological Chemistry

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RHO GTPase-activating proteins (RHOGAPs) are one of the major classes of regulators of the RHO-related protein family that are crucial in many cellular processes, motility, contractility, growth, differentiation, and development. Using database searches, we extracted 66 distinct human RHOGAPs, from which 57 have a common catalytic domain capable of terminating RHO protein signaling by stimulating the slow intrinsic GTP hydrolysis (GTPase) reaction. The specificity of the majority of the members of RHOGAP family is largely uncharacterized. Here, we comprehensively investigated the sequence-structurefunction relationship between RHOGAPs and RHO proteins by combining our in vitro data with in silico data. The activity of 14 representatives of the RHOGAP family toward 12 RHO family proteins was determined in real time. We identified and structurally verified hot spots in the interface between RHOGAPs and RHO proteins as critical determinants for binding and catalysis. We have found that the RHOGAP domain itself is nonselective and in some cases rather inefficient under cell-free conditions. Thus, we propose that other domains of RHOGAPs confer substrate specificity and fine-tune their catalytic efficiency in cells.

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Section: Discussionmentioning

confidence: 99%

Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins

Amin

Jaiswal

Derewenda

et al. 2016

Journal of Biological Chemistry

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“…43,44 Some of the top genes in our analysis, such as cystatin D (CST5) and ARHGAP36 in epithelioid sarcoma, have been previously reported to be dysregulated in cancer cells. 45,46 Yet, very little information has been published on the expression pattern or biologic function of others that we identified. TMEM215 is a transmembrane protein and therefore likely to be involved in cell signaling.…”

Section: Discussionmentioning

confidence: 99%

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Sarver

Thayanithy

et al. 2015

Laboratory Investigation

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Human sarcomas comprise a heterogeneous group of more than 50 subtypes broadly classified into two groups: bone and soft tissue sarcomas. Such heterogeneity and their relative rarity have made them challenging targets for classification, biomarker identification, and development of improved treatment strategies. In this study, we used RNA sequencing to analyze 35 primary human tissue samples representing 13 different sarcoma subtypes, along with benign schwannoma, and normal bone and muscle tissues. For each sarcoma subtype, we detected unique messenger RNA (mRNA) expression signatures, which we further subjected to bioinformatic functional analysis, upstream regulatory analysis, and microRNA (miRNA) targeting analysis. We found that, for each sarcoma subtype, significantly upregulated genes and their deduced upstream regulators included not only previously implicated known players but also novel candidates not previously reported to be associated with sarcoma. For example, the schwannoma samples were characterized by high expression of not only the known associated proteins GFAP and GAP43 but also the novel player GJB6. Further, when we integrated our expression profiles with miRNA expression data from each sarcoma subtype, we were able to deduce potential key miRNA-gene regulator relationships for each. In the Ewing's sarcoma and fibromatosis samples, two sarcomas where miR-182-5p is significantly downregulated, multiple predicted targets were significantly upregulated, including HMCN1, NKX2-2, SCNN1G, and SOX2. In conclusion, despite the small number of samples per sarcoma subtype, we were able to identify key known players; concurrently, we discovered novel genes that may prove to be important in the molecular classification of sarcomas and in the development of novel treatments.

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“…Indeed, FARP1 expression is downregulated in renal cell carcinoma, and ARHGAP36 is overexpressed in human medulloblastomas, whereas Lsc-knockout mice, the murine homolog of human ARHGEF1, display impaired B/T-lymphocyte proliferation (Francis et al 2006, Siu et al 2009, Rack et al 2014. Moreover, expression of the two other GAPs, ARHGAP8 and oligophrenin-1, are upregulated in invasive cervical cancer and glioblastoma, respectively (Ljubimova et al 2001, Song et al 2008.…”

Section: :4mentioning

confidence: 99%

“…Accordingly, the only publication on ARHGAP36 function suggested a Rho-independent role of ARHGAP36 in the Hedgehog pathway activation (Rack et al 2014). Interestingly, upregulation of the Hedgehog pathway stimulates proliferation of rat PCC cells (Carr et al 2014).…”

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confidence: 99%

Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

Croisé¹,

Houy²,

Gand³

et al. 2016

Endocrine-Related Cancer

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Among small GTPases from the Rho family, Cdc42, Rac, and Rho are well known to mediate a large variety of cellular processes linked with cancer biology through their ability to cycle between an inactive (GDP-bound) and an active (GTP-bound) state. Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated form, whereas the GTPase-activating proteins (GAPs) catalyze GTP hydrolysis, leading to the inactivated form. Modulation of Rho GTPase activity following altered expression of Rho-GEFs and/or Rho-GAPs has already been reported in various human tumors. However, nothing is known about the Rho GTPase activity or the expression of their regulators in human pheochromocytomas, a neuroendocrine tumor (NET) arising from chromaffin cells of the adrenal medulla. In this study, we demonstrate, through an ELISA-based activity assay, that Rac1 and Cdc42 activities decrease in human pheochromocytomas (PCCs) compared with the matched adjacent non-tumor tissue. Furthermore, through quantitative mass spectrometry (MS) approaches, we show that the expression of two Rho-GEF proteins, namely ARHGEF1 and FARP1, is significantly reduced in tumors compared with matched non-tumor tissue, whereas ARHGAP36 expression is increased. Moreover, siRNA-based knockdown of ARHGEF1 and FARP1 in PC12 cells leads to a significant inhibition of Rac1 and Cdc42 activities, respectively. Finally, a principal component analysis (PCA) of our dataset was able to discriminate PCC from non-tumor tissue and indicates a close correlation between Cdc42/Rac1 activity and FARP1/ARHGEF1 expression. Altogether, our findings reveal for the first time the importance of modulation of Rho GTPase activities and expression of their regulators in human PCCs. 23:4Research 281-293 P Croisé et al.Rho-GTPase activity in human pheochromocytoma

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Arhgap36-dependent activation of Gli transcription factors

Cited by 39 publications

References 47 publications

Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins

Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins

Identification, by systematic RNA sequencing, of novel candidate biomarkers and therapeutic targets in human soft tissue tumors

Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression

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