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TOMAS MUSTELIN, M.D., PH.D.
Program Director, Adjunct Professor
Inflammatory Diseases
858.795.5270 (phone)
858.795.5274 (fax)
tmustelin@burnham.org
RESEARCH FOCUS, BIOGRAPHY, STAFF, PUBLICATIONS
Research Focus
Dr. Mustelin investigates a family of genes called protein tyrosine phosphatase (PTPases), many of which act as tumor suppressors in numerous types of human cancer. It is anticipated that damage or loss of many additional family members will be found to underlay human disease, particularly cancers of white blood cells (e.g. leukemias and lymphomas). Dr. Mustelin has generated the tools to study some 35 different PTPases, representing nearly half of the genes in this family in the human genome. Dr. Mustelin's work aims at understanding the exact function of each of these PTPases in the cell's machinery for growth, survival, and death, in the white blood cell system. The results of Dr. Mustelin's research will help him and others to design rational approaches for the combat of cancer.
Biography
Tomas Mustelin earned his M.D. and Ph.D. degrees from University of Helsinki in 1987. He trained as a postdoctoral fellow at The Scripps Research Institute in La Jolla, 1988-1990. Dr. Mustelin returned to Finland for two years in clinical practice and research as a Junior Scientist with the Finnish Academy of Sciences at University of Helsinki. He was appointed Docent at University of Helsinki in 1992, an appointment he maintains to this day. From 1992-1998, Dr. Mustelin worked at La Jolla Institute of Allergy and Immunology in San Diego, as Assistant, then Associate Member. He was affiliated briefly with the Sidney Kimmel Cancer Center in San Diego prior to his recruitment to the Burnham Institute for Medical Research in September 1999.
Selected Publications
Bottini,
N., Musumeci, L., Alonso, A., Rahmouni, S., Nika, K., Rostamkhani, M.,
MacMurray, J., Meloni, G.F., Lucarelli, P., Pellecchia, M., Eisenbarth,
G.S., Comings, D. & Mustelin, T. (2004). A functional variant of
lymphoid tyrosine phosphatase is associated with type I diabetes.
Nature Genetics 36, 337-338.
Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I.,
Osterman, A., Godzik, A., Hunter, T., Dixon, J.E., and Mustelin, T.
(2004). Protein tyrosine phosphatases in the human genome. Cell 117,
699-720.
Alonso, A., Rahmouni, S., Williams, S., van Stipdonk, M., Jaroszewski, L.,
Godzik, A., Abraham, R.T., Schoenberger, S.P. & Mustelin, T.
(2003). Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nature
Immunology 4, 44-48.
Mustelin, T., Coggeshall, K.M., Isakov, N. and Altman, A. Tyrosine
phosphorylation is required for T cell antigen receptor-mediated activation of phospholipase C. Science 247:1584-1587, 1990.
Saxena, M., Williams, S., Taskén, K., and Mustelin, T. Crosstalk
between cAMP-dependent kinase and MAP kinase through hematopoietic protein
tyrosine phosphatase (HePTP). Nature Cell Biol. 1:305-311, 1999.
Virolle, T., Adamson, E.D., Baron, V., Birle, D., Mercola, D., Mustelin, T.
& de Belle, I. PTEN is directly transactivated in vivo by Egr-1
during irradiation-induced signalling. Nature Cell Biol. 3:1124-1128, 2001.
List of Publications via PubMed
(NIH National Library of Medicine)
Research Report
SIGNAL TRANSDUCTION AND REVERSIBLE PHOSPHORYLATION
(Download report as PDF)
This laboratory investigates the molecular mechanisms of signal transduction
from the T cell antigen receptor that lead to gene activation and
initiation of cell growth.
Tyrosine phosphorylation
Phosphorylation
of key proteins and enzymes on specific tyrosine residues is a
fundamental mechanism whereby cells control their growth, proliferation
and differentiation. This control is lost in cancer. Extracellular
growth stimuli, such as growth factors or antigens, affect cells by
inducing a rapid
but transient tyrosine phosphorylation of a number of regulatory
proteins. We have shown that inhibition of this phosphorylation
prevents antigen receptor-initiated lymphoid cell activation and
proliferation altogether, indicating that enhanced tyrosine
phosphorylation is a prerequisite for initiating the cascade of
biochemical events leading to activation of the lymphocyte's effector
functions and clonal proliferation. A deeper understanding of these
events will form a basis for a rational design of pharmacological or
other means to manipulate T cell activation and proliferation as part
of treatment of various diseases or conditions where the lymphoid
system plays a part, such as T cell leukemias, dysfunction of the
immune system in cancer patients, other immunodeficiencies,
autoimmunity etc. Our progress may also be helpful in a broader sense
since the same or similar molecules and pathways also operate in other
cells.
Protein tyrosine phosphatases (PTPases)
Since phosphorylation of cellular proteins on tyrosine residues plays a
very fundamental role both in determining the responsiveness of T cells
to receptor triggering, as well as the initiation and maintenance of
cell proliferation, the role of PTPases in T cell physiology is
obviously crucial. It is important to note, however, that PTPases may
function both as positive and negative regulators of T cell functions,
and a more detailed understanding of the T cell-expressed PTPases and
their physiological substrates and roles will add to our knowledge on
the overall function of these proteins.
Following earlier work on CD45 and its function in T cell activation,
we recently entered this field more broadly by systematically
determining which of all
the known PTPases are expressed in T lymphocytes. Subsequently, the
cDNAs for the PTPases that were found to be present were isolated in
the lab or obtained from other scientists. Using these cDNAs (currently
CD45, SHP1, SHP2, TCPTP, HePTP, PEP, Lyp1, Lyp2, PTP-MEG2, PTP-MEG1,
PTPH1, PTP36, VHR, MKP-1, PTEN, PRL-1, OV-1 and LMPTP-A, -B, and -C),
we are in the process of analyzing their potential role in the early
events of TCR-mediated signal transduction. So far, results suggest
that as many as eleven of these enzymes participate at various steps in
signal transmission. We will investigate these in detail and determine
their exact sites of action, their regulation and their importance. The
planned work includes the generation of mice deficient in the
expression of specific PTPases ('knock-out') as well as basic molecular
biology and biochemical characterization of the enzymes. Our group will
also continue to study the observation that 1) several PTPases
(including CD45, SHP1, SHP2 and LMPTP) are regulated by tyrosine
phosphorylation and therefore must interact with PTKs, 2) the finding
that HePTP associates physically
with, and regulates, the MAP kinases Erk and p38, and 3) that
phosphorylation of SHP2 induces its association with three proteins
that are important in T cell activation, namely PI3K, Grb2 and Vav.
This suggests that PTPase targeting can be actively regulated during
signal transmission. We are also interested in studying PTPases
involved in integrin signaling, adhesion, cell migration, malignant
transformation, and other physiological processes regulated by
reversible tyrosine phosphorylation.
Protein tyrosine kinases (PTKs)
We have a long-standing interest in the PTKs that are instrumental to T
cell activation. Several of these kinases are encoded by protooncogenes
and have been shown to cause malignant transformation in laboratory
models as well as in patients suffering from T cell lymphomas and
leukemias. We have published papers documenting the role and regulation
of the Src family kinases Lck and Fyn,
the Syk-family kinases Syk and Zap-70, and the Csk kinase. Current work
focuses on the physical and functional interactions between these PTKs,
their regulation and their substrates. Experiments will also address
the redundancy versus specificity of family members and their
differential expression in subsets of lymphocytes.
Phosphatidylinositol
3-kinase and the PTEN tumor suppressor Phosdphatidylinositol 3-kinase
(PI3K), a signal transducing molecule regulated by PTKs and PTPases,
has been another center of attention in our laboratory for several
years. This lipid
kinase is also known to participate in signals that govern cell growth
and differentiation in many other cell types. We have found that PI3K
plays an active positive role in T cell activation by augmenting the
TCR-induced activation of the MAP kinase Erk2. Studies on the mechanism
of this involvement have revealed that TCR-induced tyrosine
phosphorylation of the 36-38-kDa LAT protein is responsible for the
recruitment and activation of PI3K. Current work addresses the role of
the PTEN phosphatase, which antagonizes PI3K by dephosphorylating its
products. This protein is a well-established tumor suppressor, which is
deficient in a large portion of human cancers. PTEN expression induces
rapid
apoptosis in T cells. Other areas under investigation are: 1) the
regulation of PI3K by phosphorylation of one of its SH2 domains, 2) the
role of PI3K products in the recruitment of other signaling molecules
(e.g. PLCg1, Vav and Itk) to the plasma membrane, 3) the relationship
between PI3K, Ras and Rac, 4) the association of PI3K with SHP2, and 5)
the hypothesis that the PI3K-stimulated MEKK2 kinase is a component in
MAP kinase activation in T cells.
Confocal microscopy of Jurkat cells transfected with empty pEF/HA vector (panel a), or expression plasmids encoding the indicated PTPases and stained with a FITC-anti-HA mAb (panels a - o). Panels p and q represent COS cells expressing TCPTP or PTP-MEG2 and stained with the FITC-anti-HA mAb.
