PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK

Cho, Eunice; Lou, Hua; Kuruvilla, Leena; Calderwood, David A.

doi:10.1016/j.celrep.2021.108928

Cited by 23 publications

(35 citation statements)

References 97 publications

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“…The PP6 complex is widely expressed in many tissue types and has been implicated in diverse processes such as cell cycle, inflammatory signaling, and lymphocyte development 7 – 9 . Recent studies suggest that PPP6C mutations affect its activity and participate in melanoma tumorigenesis through resulting MEK hyperphosphorylation 10 . However, its role in a melanocyte-specific developmental context has not been studied extensively, and the role that the R264C recurrent mutation plays in disease progression has not been the focus of intense study.…”

Section: Introductionmentioning

confidence: 99%

PPP6C, a serine-threonine phosphatase, regulates melanocyte differentiation and contributes to melanoma tumorigenesis through modulation of MITF activity

Maskin

Raman

Houvras

2022

Sci Rep

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It is critical to understand the molecular mechanisms governing the regulation of MITF, a lineage specific transcription factor in melanocytes and an oncogene in melanoma. We identified PPP6C, a serine/threonine phosphatase, as a key regulator of MITF in melanoma. PPP6C is the only recurrently mutated serine/threonine phosphatase across all human cancers identified in sequencing studies and the recurrent R264C mutation occurs exclusively in melanoma. Using a zebrafish developmental model system, we demonstrate that PPP6C expression disrupts melanocyte differentiation. Melanocyte disruption was rescued by engineering phosphomimetic mutations at serine residues on MITF. We developed an in vivo MITF promoter assay in zebrafish and studied the effects of PPP6C(R264C) on regulating MITF promoter activity. Expression of PPP6C(R264C) cooperated with oncogenic NRAS(Q61K) to accelerate melanoma initiation in zebrafish, consistent with a gain of function alteration. Using a human melanoma cell line, we examined the requirement for PPP6C in proliferation and MITF expression. We show that genetic inactivation of PPP6C increases MITF and target gene expression, decreases sensitivity to BRAF inhibition, and increases phosphorylated MITF in a BRAF(V600E) mutant melanoma cell line. Our data suggests that PPP6C may be a relevant drug target in melanoma and proposes a mechanism for its action.

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Section: Introductionmentioning

confidence: 99%

PPP6C, a serine-threonine phosphatase, regulates melanocyte differentiation and contributes to melanoma tumorigenesis through modulation of MITF activity

Maskin

Raman

Houvras

2022

Sci Rep

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“…Fibroblast growth factor receptor 3 (FGFR3) is a well-established cancer driver gene in several cancers, and single molecule inhibitors of this gene are used as therapeutic agents [ 69 ]. Protein phosphatase 6 (PP6 encoded by PPP6C) encodes the catalytic subunit of a PP2A like phosphatase [ 70 ], a molecular regulator of RAS and other RAS associated pathways (e.g., BRAF/MEK/ERK) involved in cell proliferation [ 71 ]. PP6 participates in many processes including DNA damage repair, inflammation, and the immune response, and PP6 mutations are associated with tumor progression [ 72 ].…”

Section: Resultsmentioning

confidence: 99%

Arginine Depletion in Human Cancers

Nelakurti

Rossetti

Husbands

et al. 2021

Cancers

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Arginine is encoded by six different codons. Base pair changes in any of these codons can have a broad spectrum of effects including substitutions to twelve different amino acids, eighteen synonymous changes, and two stop codons. Four amino acids (histidine, cysteine, glutamine, and tryptophan) account for over 75% of amino acid substitutions of arginine. This suggests that a mutational bias, or “purifying selection”, mechanism is at work. This bias appears to be driven by C > T and G > A transitions in four of the six arginine codons, a signature that is universal and independent of cancer tissue of origin or histology. Here, we provide a review of the available literature and reanalyze publicly available data from the Catalogue of Somatic Mutations in Cancer (COSMIC). Our analysis identifies several genes with an arginine substitution bias. These include known factors such as IDH1, as well as previously unreported genes, including four cancer driver genes (FGFR3, PPP6C, MAX, GNAQ). We propose that base pair substitution bias and amino acid physiology both play a role in purifying selection. This model may explain the documented arginine substitution bias in cancers.

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“…That raises an intriguing possibility that ANKRD28/PP6 directly dephosphorylates pFAK-S910. Another possibility is that ERK activity is decreased in Rab40c-KO cells because PP6 has recently been identified as a key negative regulator of ERK signaling by dephosphorylating MEK ( Cho et al, 2021 ). Thus, although additional studies will be needed to determine the mechanisms of PP6-dependent FAK regulation, our data imply that the Rab40c-ANKRD28/PP6 pathway contributes to regulating FAK activity and FA disassembly during cancer cell migration ( Fig 8G ).…”

Section: Discussionmentioning

confidence: 99%

Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation

et al. 2022

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Rab40c is a SOCS box–containing protein which binds Cullin5 to form a ubiquitin E3 ligase complex (Rab40c/CRL5) to regulate protein ubiquitylation. However, the exact functions of Rab40c remain to be determined, and what proteins are the targets of Rab40c-Cullin5–mediated ubiquitylation in mammalian cells are unknown. Here we showed that in migrating MDA-MB-231 cells Rab40c regulates focal adhesion’s number, size, and distribution. Mechanistically, we found that Rab40c binds the protein phosphatase 6 (PP6) complex and ubiquitylates one of its subunits, ankyrin repeat domain 28 (ANKRD28), thus leading to its lysosomal degradation. Furthermore, we identified that phosphorylation of FAK and MOB1 is decreased in Rab40c knock-out cells, which may contribute to focal adhesion site regulation by Rab40c. Thus, we propose a model where Rab40c/CRL5 regulates ANKRD28 ubiquitylation and degradation, leading to a decrease in PP6 activity, which ultimately affects FAK and Hippo pathway signaling to alter focal adhesion dynamics.

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PPP6C negatively regulates oncogenic ERK signaling through dephosphorylation of MEK

Cited by 23 publications

References 97 publications

PPP6C, a serine-threonine phosphatase, regulates melanocyte differentiation and contributes to melanoma tumorigenesis through modulation of MITF activity

PPP6C, a serine-threonine phosphatase, regulates melanocyte differentiation and contributes to melanoma tumorigenesis through modulation of MITF activity

Arginine Depletion in Human Cancers

Rab40c regulates focal adhesions and PP6 activity by controlling ANKRD28 ubiquitylation

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