PXD014736

PXD014736 is an original dataset announced via ProteomeXchange.

Title	c-Met activation leads to the establishment of a TGFβ receptor regulatory network required for bladder cancer invasion
Description	Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the precise mechanisms underlying HGF/c-MET mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to the E3 ligase SMURF2 targeting the TGFβ receptor for degradation. Under these conditions SMAD7 acts as an agonist disrupting the intermolecular interactions within SMURF2, permitting SMURF2 activation. We demonstrate that HGF stimulates TGFβ signaling by inducing c-SRC mediated phosphorylation of SMURF2 at two tyrosine residues impeding SMAD7 binding and enhancing SMURF2 C2-HECT domain interaction, resulting in SMURF2 inhibition and TGFβ receptor stabilization. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. Using biologically relevant orthotopic mouse models we show that inhibition of TGFβ signaling completely prevents HGF induced bladder cancer invasion. Furthermore, we make a rationale for the use of TGFβ receptor and MEK inhibitors in the treatment of high grade non-muscle-invasive bladder cancers or early stage muscle invasive bladder cancers.
HostingRepository	PRIDE
AnnounceDate	2019-08-26
AnnouncementXML	Submission_2019-08-26_00:19:53.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Dennis Kappei
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	6x(13)C: 4x(15)N labeled L-arginine; 6x(13)C: 2x(15)N labeled L-lysine; phosphorylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-24 08:01:31	ID requested
⏵ 1	2019-08-26 00:19:54	announced

Dataset with its publication pending

submitter keyword: Bladder cancer invasion, EMT, c-MET, TGFB, SMURF2, phosphorylation

Dennis Kappei
contact affiliation	Cancer Science Institute of Singapore (CSI), National University of Singapore (NUS)
contact email	dennis.kappei@nus.edu.sg
lab head
Dennis Kappei
contact affiliation	Cancer Science Institute of Singapore
contact email	dennis.kappei@nus.edu.sg
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014736
     1. Label: PRIDE project
     2. Name: c-Met activation leads to the establishment of a TGFβ receptor regulatory network required for bladder cancer invasion