PXD035415

PXD035415 is an original dataset announced via ProteomeXchange.

Title	Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells
Description	The protein kinases PAK4, PAK5 and PAK6 comprise a family of ohnologues. In multiple cancers including melanomas PAK5 most frequently carries non‐synonymous mutations; PAK6 and PAK4 have fewer; and PAK4 is often amplified. To help interpret these genomic data, initially we compared the cellular regulation of the sister kinases and their roles in melanoma cells. In common with many ohnologue protein kinases, PAK4, PAK5 and PAK6 each have two 14‐3‐3‐binding phosphosites of which phosphoSer99 is conserved. PAK4 localises to the leading edge of cells in response to phorbol ester‐ stimulated binding of 14‐3‐3 to phosphoSer99 and phosphoSer181, which are phosphorylated by two different PKCs or PKDs. These phosphorylations of PAK4 are essential for its phorbol ester‐stimulated phosphorylation of downstream substrates. In contrast, 14‐3‐3 interacts with PAK5 in response to phorbol ester‐stimulated phosphorylation of Ser99 and epidermal growth factor‐stimulated phosphorylation of Ser288; whereas PAK6 docks onto 14‐3‐3 and is prevented from localising to cell‐cell junctions when Ser133 is phosphorylated in response to cAMP‐elevating agents via PKA and insulin‐like growth factor 1 via PKB/Akt. Silencing of PAK4 impairs proliferation, migration and invasive behaviour of melanoma cells carrying BRAFV600E or NRASQ61K mutations. These defects are rescued by ectopic expression of PAK4, more so by a 14‐3‐3‐binding deficient PAK4, and barely by PAK5 or PAK6. Together these genomic, biochemical and cellular data suggest that the oncogenic properties of PAK4 are regulated by PKC–PKD signalling in melanoma, while PAK5 and PAK6 are dispensable in this cancer.
HostingRepository	PRIDE
AnnounceDate	2022-09-01
AnnouncementXML	Submission_2022-09-01_07:18:04.598.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Carol MacKintosh
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-20 00:58:28	ID requested
⏵ 1	2022-09-01 07:18:05	announced

Murugesan G, Prescott AR, Toth R, Campbell DG, Wells CM, MacKintosh C, Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells. Biochem J, 479(16):1709-1725(2022) [pubmed]

submitter keyword: 14‐3‐3, melanoma, ohnologue/ohnolog, PAK4, PAK5 (also known as PAK7, PAK6, signalling networks

Carol MacKintosh
contact affiliation	Cell and Developmental Biology, School of Life Sciences, University of Dundee, DD1 4HN
contact email	c.mackintosh@dundee.ac.uk
lab head
Carol MacKintosh
contact affiliation	Cell and Developmental Biology, School of Life Sciences, University of Dundee Dundee DD1 4HN
contact email	c.mackintosh@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035415
     1. Label: PRIDE project
     2. Name: Differential roles and regulation of the protein kinases PAK4, PAK5 and PAK6 in melanoma cells