Lim Yoon Pin’s laboratory of Molecular and Translational Cancer Research

Research



How WBP2 was discovered

A. WBP2, a novel breast cancer oncogene


A1. How WBP2 was discovered:


How WBP2 was discovered
how WBP2 was discovered


A2. Salient features of WBP2:


A. Structural Organization


Structural Organization
Structural Organization

  • Binds to WW-domain-containing protein
    1. Identified and cloned as ligand protein for YAP WW domain
  • Regulatory or signaling role via protein-protein interaction
    1. GRAM (Glucosyltransferase, RAb-like GTPase Activators and Myotubularins) Domain
      1. Intracellular protein binding or lipid binding signaling domain
      2. Potential role in membrane-coupled processes and signal transduction
  • PY motif
    1. Three proline-rich motifs (PY1-3)
    2. Consensus sequence: PPXY
    3. Evolutionarily well conserved
    4. Binding recognition sites for WW domain-containing protein
    5. Mediates protein-protein interaction
    6. Potential role in transcriptional activation



B. Biological Function




A3. Proposed model of the signaling pathways and mode of action of WBP2:


Lim SK, Orhant-Prioux M, Toy W, Tan KY, Lim YP. FASEB J. 2011 Jun 9. [Epub ahead of print]
Proposed model of the signaling pathways and mode of action of WBP2

* Lim SK, Orhant-Prioux M, Toy W, Tan KY, Lim YP. FASEB J. 2011 Jun 9. [Epub ahead of print]

EGFR is either activated directly by EGF stimulation (1) or indirectly by estrogen via ER-EGFR crosstalk (2), leading to the activation of its downstream c-Src and c-Yes tyrosine kinase (3). c-Src could alternatively act upstream of EGFR to modulate EGFR-dependent tyrosine phosphorylation of WBP2 (4). In conjunction with YAP, activated c-Yes binds to and phosphorylate WBP2 at Tyr192 and Tyr231(5). Phospho-Y192-231 WBP2 enters into nucleus and interacts with ER (6), resulting in increased ER transactivation and estrogen-dependent gene transcription (7). Phospho-Y192-231 WBP2 also promotes the Wnt pathway activation (8), which subsequently cross-talk to ER pathway (9). On the other hand, phospho-Y192-231 WBP2 could also transcriptionally potentiate other oncogenic signaling pathways (10) which are crucial for cell cycle control, apoptosis, cell migration and invasion, leading to uncontrolled breast cancer growth (11).




A4. Future directions for WBP2


  • Mapping out transcription regulatory role of WBP2
  • Expanding the functional link between WBP2 and other oncogenic pathways
  • Establishing WBP2 as an oncogene in other cancer types
  • Developing WBP2 as companion diagnostics and/or drug target




B. Biomarker and drug target discovery



Gastric cancer plasma proteomics and biomarker discovery using clinical samples


  1. C9 is a potentially useful biomarker for gastric cancer detection.
  2. C9 expression level found to be significantly higher in gastric cancer patients compared to normal subject.



Plasma proteomics on xenograft model of Gastric cancer for biomarker discovery



Plasma proteomics on xenograft model of Gastric cancer for biomarker discovery

  1. ITIH3 protein was found to be highly expressed in tumor-bearing mice compared to control.
  2. Validation using clinical samples also revealed higher ITIH3 expression level in gastric cancer patients compared to normal subjects.


Secretome analysis and discovery of drug targets in gastric cancer



Secretome analysis and discovery of drug targets in gastric cancer

  1. CTSS plays a novel role in gastric cancer invasion.
  2. Subsequent secretomics revealed novel targets of CTSS that may mediate gastric cancer invasion.




C. A cell surface channel as a novel breast cancer metastasis effecter

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