PAK4 promotes kinase-independent stabilization of RhoU to modulate cell adhesion

Dart, Anna; Box, Gary; Court, William; Gale, Madeline E.; Brown, John P.; Pinder, Sarah; Eccles, Suzanne A.; Wells, Claire M.

doi:10.1083/jcb.201501072

Cited by 68 publications

(88 citation statements)

References 63 publications

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“…Phospho-PAK4 (pS474) levels are unchanged upon RhoU overexpression, indicating that PAK4 is not a RhoU effector protein. 15 Instead, PAK4 plays an unconventional kinase-independent role in RhoU regulation. PAK4 regulates RhoU expression levels by protecting RhoU from Rab40A-mediated proteasomal degradation.…”

Section: Binding Partnersmentioning

confidence: 99%

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Regulation and functions of RhoU and RhoV

Hodge

Ridley

2017

Small GTPases

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Rho GTPases play central roles in a wide variety of cellular processes, including cytoskeletal dynamics, cell adhesion and cell polarity. RhoU and RhoV are Rho GTPases that have some atypical properties compared with classical Rho family members, such as the presence of N-and C-terminal extension regions, unusual GDP/GTP cycling and post-translational modification by palmitoylation but not prenylation. Their activity and localization is regulated by the N-terminal and C-terminal regions, and so far no GEFs or GAPs have been identified for them. Similar to Rac and Cdc42, they interact with PAK serine/threonine kinases, and in the case of PAK4, this interaction leads to RhoU protein stabilization. In cells, RhoU and RhoV alter cell shape and cell adhesion, which probably underlies some of the phenotypes reported for these proteins in vivo, for example in heart development and epithelial morphogenesis. However, the molecular basis for these functions of RhoU and RhoV remains to be characterized.

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Section: Binding Partnersmentioning

confidence: 99%

“…PAK4 regulates RhoU expression levels by protecting RhoU from Rab40A-mediated proteasomal degradation. 15 RhoU stabilization by PAK4 leads to stimulation of MDA-MB-231 breast cancer cell migration and promotes focal adhesion turnover.…”

Section: Binding Partnersmentioning

confidence: 99%

Regulation and functions of RhoU and RhoV

Hodge

Ridley

2017

Small GTPases

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“…96,102 Other known binding partners for RhoU and RhoV are the PAK family of kinases, which also interact with Cdc42 and Rac. 47,95,103,104 RhoH, also known as TTF (translocation 3 4), is expressed predominantly in haematopoietic tissues, similarly to Rac2. 105 RhoH is GTPase-deficient, and is therefore assumed to be constantly in a GTP-bound form.…”

Section: Functions and Regulation Of Atypical Rho Gtpasesmentioning

confidence: 99%

Rho GTPases: Regulation and roles in cancer cell biology

Haga

Ridley²

2016

Small GTPases

417

390

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Rho GTPases are well known for their roles in regulating cell migration, and also contribute to a variety of other cellular responses. They are subdivided into 2 groups: typical and atypical. The typical Rho family members, including RhoA, Rac1 and Cdc42, cycle between an active GTP-bound and inactive GDP-bound conformation, and are regulated by GEFs, GAPs and GDIs, whereas atypical Rho family members have amino acid substitutions that alter their ability to interact with GTP/GDP and hence are regulated by different mechanisms. Both typical and atypical Rho GTPases contribute to cancer progression. In a few cancers, RhoA or Rac1 are mutated, but in most cancers expression levels and/or activity of Rho GTPases is altered. Rho GTPase signaling could therefore be therapeutically targeted in cancer treatment.

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“…Dart et al 112 show that reduced expression of PAK4 leads to loss of RHOU and RHOU is ubiquitinated via RAB40A-CULLIN5 complex. Expression of PAK4 rescues RHOU ubiquitination.…”

Section: Dicationmentioning

confidence: 99%

“…PAK4 has been found to be expressed in breast cancer cells and depletion of the same modifies cell adhesion dynamics 112 . Dart et al 112 show that reduced expression of PAK4 leads to loss of RHOU and RHOU is ubiquitinated via RAB40A-CULLIN5 complex.…”

Section: Dicationmentioning

confidence: 99%

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stemness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2 nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1 , we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2 nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3 rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3 rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest. KEYWORDS -WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking Conference, from 6-11 August 2017, held Significance WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. Often, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be involved in the pathway. The current work reveals at in silico level, the 3rd order WNT10B associated combinations that might be affected by the admin...

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PAK4 promotes kinase-independent stabilization of RhoU to modulate cell adhesion

Abstract: PAK4, via a novel kinase-independent mechanism, protects RhoU from a Rab40A/Cullin 5 ubiquitin ligase complex–driven K48 ubiquitination to regulate breast cancer cell adhesion.

Cited by 68 publications

References 63 publications

Regulation and functions of RhoU and RhoV

Regulation and functions of RhoU and RhoV

Rho GTPases: Regulation and roles in cancer cell biology

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

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