• Pallen, Catherine J.

    Titles
    Investigator, Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital
    Professor, Division of Hematology and Oncology, Department of Pediatrics, University of British Columbia
    Associate Member, Department of Pathology and Laboratory Medicine, University of British Columbia
    Scientist, Michael Cuccione Childhood Cancer Research Program
    Degrees / Designations
    PhD
    Primary Area of Research
    Childhood Diseases
    Secondary Area(s) of Research
    Phone
    604-875-2439
    Fax
    604-875-2417
    Lab Phone
    604-875-2485
    Assistant
    Sara Doherty
    Assistant Phone
    604-875-3886
    Mailing Address

    BC Children's Hospital Research Institute\
    Room 3102
    950 West 28th Avenue
    Vancouver, BC V5Z 4H4

    Affiliate Websites
    Research Areas

    Protein tyrosine phosphatases in cell signalling, health, and disease.

    Summary

    Reversible protein tyrosine phosphorylation is a prominent mechanism utilized in controlling these signalling pathways: protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) co-ordinately determine the tyrosine phosphorylation status and the function of a particular substrate protein. Perturbations of such signalling pathways underlie a variety of pathological conditions. Aberrant tyrosine phosphorylation due to malfunctioning PTKs is well established as the basis of several human diseases, in particular human cancers. It is becoming apparent that defective or deregulated PTPs are likewise critical in the development and progression of some human diseases such as cancer and diabetes. Consequently, PTPs are excellent targets for disease intervention.

    Current Projects

    The lab studies the molecular, cell, and whole animal biology of selected PTPs, in particular the receptor PTPa and the prenylated PRL-PTPs. Characterizing their substrates, pathways of action, regulation, and localization will shed light on their specific cellular and physiological roles, reveal linkages with human pathophysiologies, and facilitate the development of PTP-based disease therapies.  We are particularly interested in the roles of PTPs in pediatric malignancies.

    We have identified the transmembrane PTPa as a potential oncogene and as a physiological activator of the proto-oncogene src family kinases.  We are elucidating the signal transduction and biological functions of PTPa using PTPa knockout mice and cells that we have generated.  One line of study involves the role of PTPa in integrin signalling. Integrins are essential for several cell processes, including growth, migration, and survival.  They are thus positioned to determine, and have indeed been implicated in, multiple aspects of cancer cell biology such as invasion and metastasis.  In the absence of PTPa, integrin stimulated cell migration and spreading are defective due to impaired early and integrin-proximal signalling events.  The molecular basis of these defects is under investigation.  Other studies are pursuing the linkage of additional novel defects observed in the PTPa knockout mice to altered cell signalling pathways and function in neurobiology (myelination, NMDA receptor function) and immunology (T cell activation, mast cell function).

    The intracellular PRL-PTPs (PRL-1, -2, -3) are closely related prenylated PTPs of unknown function. PRL-3 expression has been recently found to be upregulated in several metastatic cancers.  Farnesyltransferase inhibitors (FTI) are anti-tumor agents that were originally designed to block the function of the ras oncogene product.  However, in many tumors, these inhibitors act on unidentified non-ras targets.  We have shown that the PRLs are potential targets of these inhibitors.  FTI induces the relocalization of the PRL-PTPs from the plasma membrane and early endosome to the nucleus, with the likely consequence of altering substrate availability and/or PRL-PTP functions.  Our studies are directed to identifying plasma membrane/early endosome-specific versus nuclear-specific PRL-PTP substrates and interacting proteins.  This will pinpoint alternate PRL-PTP functions and signalling pathways that may be relevant to tumorigenesis or tumor progression. Additionally, we are examining PRL-PTP expression in a range of primary and metastatic tumors to ascertain whether altered PRL-PTP levels correlate with malignancy status.

    Selected Publications

    For the latest publications, please visit Dr. Pallen’s ORCID profile.

    Cheng SY, Sun G, Schlaepfer DD, Pallen CJ. Grb2 Promotes Integrin-Induced Focal Adhesion Kinase (FAK) Autophosphorylation and Directs the Phosphorylation of Protein Tyrosine Phosphatase ¦Á by the Src-FAK Kinase Complex. Mol Cell Biol. 2014 Feb;34(3):348-61. doi: 10.1128/MCB.00825-13. Epub 2013 Nov 18. PubMed PMID: 24248601.

    Meyer DS, Aceto N, Sausgruber N, Brinkhaus H, M¨¹ller U, Pallen CJ, Bentires-Alj M. Tyrosine phosphatase PTP¦Á contributes to HER2-evoked breast tumor initiation and maintenance. Oncogene. 2014 Jan 16;33(3):398-402. doi: 10.1038/onc.2012.585. Epub 2013 Jan 14. PubMed PMID: 23318421.

    Fam HK, Walton C, Mitra SA, Chowdhury M, Osborne N, Choi K, Sun G, Wong PC, O'Sullivan MJ, Turashvili G, Aparicio S, Triche TJ, Bond M, Pallen CJ, Boerkoel CF. TDP1 and PARP1 deficiency are cytotoxic to rhabdomyosarcoma cells. Mol Cancer Res. 2013 Oct;11(10):1179-92. doi: 10.1158/1541-7786.MCR-12-0575. Epub 2013 Aug 2. PubMed PMID: 23913164.

    Samayawardhena LA, Pallen CJ.: Protein-tyrosine phosphatase alpha regulates stem cell factor-dependent c-Kit activation and migration of mast cells. J Biol Chem. 2008 Oct 24;283(43):29175-85.

    Bessette DC, Qiu D, Pallen CJ.: PRL PTPs: Mediators and markers of cancer progression. Cancer Metastasis Rev. 2008 Jun;27(2):231-52.

    Ye H, Tan YJL, Ponniah S, Takeda Y, Wang SQ, Schachner M, Watanabe K, Pallen CJ, Xiao ZC. (2008) Neural recognition molecules CHL1 and NB-3 regulate apical dendrite orientation in the neocortex via PTPalpha. EMBO J. 27: 188-200.

    Maksumova L, Wang Y, Wong NK, Le HT, Pallen CJ, Johnson P. (2007) Differential function of PTPalpha and PTPalpha Y789F in T cells and regulation of PTPalpha phosphorylation at Tyr789 by CD45. J Biol Chem. 282:20925-32.

    Le HT, Maksumova L, Wang J, Pallen CJ. (2006) Reduced NMDA receptor tyrosine phosphorylation in PTPalpha-deficient mouse synaptosomes is accompanied by inhibition of four src family kinases and Pyk2: an upstream role for PTPalpha in NMDA receptor regulation. J Neurochem. 98:1798-809.

    Chen M, Chen SC, Pallen CJ. (2006) Integrin-induced tyrosine phosphorylation of protein-tyrosine phosphatase-alpha is required for cytoskeletal reorganization and cell migration. J Biol Chem. 281:11972-80.

    Maksumova L, Le HT, Muratkhodjaev F, Davidson D, Veillette A, Pallen CJ. (2005) Protein tyrosine phosphatase alpha regulates Fyn activity and Cbp/PAG phosphorylation in thymocyte lipid rafts.  J Immunol. 175:7947-56.

    Le HT, Ponniah S, Pallen CJ.  (2004) Insulin signalling and glucose homeostasis in mice lacking protein tyrosine phosphatase alpha.  Biochem Biophys Res Commun. 6;314(2):321-9.

    Skelton MR, Ponniah S, Wang DZ, Doetschman T, Vorhees CV, Pallen CJ. (2003) Protein tyrosine phosphatase alpha (PTP alpha) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety. Brain Res. 984: 1-10.

    Zeng L, Si X, Yu WP, Le TH, Ng KP, Teng RMH, Ryan K, Wang DZM, Ponniah S, Pallen CJ. (2003) PTPalpha regulates integrin-stimulated FAK autophosphorylaiton and cytoskeletal rearrangement in cell spreading and migration. J. Cell. Biol. 160:137-46.

    Pallen CJ. (2003) Protein tyrosine phosphatase alpha (PTPalpha): A src family kinase activator and mediator of multiple biological effects. Curr. Top. Med. Chem. 7:821-35.

    Grants

    Cancer Research Society Grant

    Honours & Awards

    Outstanding University Researcher Award 1999/2000, National University of Singapore - 2001
    MacMillan Distinguished Lecturer, Rutgers University - 2000
    National Science Award, Singapore - 1995
    Medical Research Council of Canada Postdoctoral Fellowship - 1986-88
    Medical Research Council of Canada Studentship Award - 1982-85

    Research Group Members

    Jing Wang, PhD - Lab Manager
    Dexin Qiu, PhD – Postdoctoral Fellow
    Lionel Samayawardhena, PhD – Postdoctoral Fellow
    Darrell Bessette, MSc – Graduate Student
    Pei-Shan Wang – Graduate Student
    Suzanne Cheng – Graduate Student
    Guobin Sun – Graduate Student