Current Topics in Medicinal Chemistry, Volume 3, No. 7, 2003
Contents
Protein
Tyrosine Phosphatases as Therapeutic Targets
Guest
Editor: Scott Taylor
An Overview of
the Protein Tyrosine Phosphatase Superfamily Pp.739-748
Wei-Qing Wang, Jin-Peng Sun and Zhong-Yin Zhang
Protein
Tyrosine Phosphatase 1B: A Novel Target for Type 2 Diabetes and Obesity Pp.749-757
Chidambaram Ramachandran and Brian P. Kennedy
Inhibitors of
Protein Tyrosine Phosphatase 1B (PTP1B) Pp.759-782
Scott D. Taylor
CD45 Regulated
Signaling Pathways
Pp.783-796
Junko Irie-Sasaki , Takehiko Sasaki and Josef M. Penninger
CD45
Protein-Tyrosine Phosphatase Inhibitor Development Pp.797-807
Kyeong Lee and Terrence R. Burke, Jr.
The Leukocyte
Common Antigen-Related Protein LAR: Candidate PTP for Inhibitory Targeting Pp.809-819
Charles M. LeVea and Robert A. Mooney
Protein
Tyrosine Phosphatase α (PTPα): A Src Family Kinase Activator and Mediator of Multiple Biological Effects
Pp.821-835
Catherine J. Pallen
Abstracts
[Back to top] An
Overview of the Protein Tyrosine Phosphatase Superfamily
Wei-Qing Wang, Jin-Peng Sun and Zhong-Yin Zhang
The human genome encodes approximately
100 phosphatases that belong to the protein tyrosine phosphatase (PTP)
superfamily, whose substrates range from proteins to phosphoinositides and
mRNAs. The hallmark for this superfamily is the active site sequence C(X)5R,
also known as the PTP signature motif. The PTPs are key regulatory components
in signal transduction pathways and the importance of PTPs in the control of
cellular signaling is well established. Furthermore, there are compelling
reasons to believe that PTP inhibitors may serve as novel medicinal agents for
the treatment of various diseases. Based on structure and substrate
specificity, the PTP super-family is divided into four distinct subfamilies: 1)
pTyr specific PTPs, 2) dual specificity phosphatases, 3) Cdc25 phosphatases,
and 4) LMW PTPs. The PTPs have similar core structures made of a central
parallel b- sheet with flanking a-helices containing a b-loop-a
loop that encompasses the PTP signature motif. Not surprisingly, they employ a
common chemical mechanism for phosphate hydrolysis despite the differences in
substrate specificity. Despite the conserved structural and catalytic
properties, there are also sufficient differences in the active site pockets
and its immediate surrounding environment among different PTPs. Further
structural and mechanistic study will continue to be of considerable
importance, providing a solid basis for inhibitor design.
[Back to top] Protein Tyrosine
Phosphatase 1B: A Novel Target for Type 2 Diabetes and Obesity
Chidambaram Ramachandran and Brian P. Kennedy
The identification of
autophosphorylation of the insulin receptor as a pivotal component in the
signal transduction induced by insulin, initiated the hunt to identify the
tyrosine phosphatase(s) that were responsible for regulating dephosphorylation,
and thus inactivation of the receptor. Compelling evidence for the existence of
an insulin receptor specific PTP has come from the remarkable phenotype of the
PTP1B deficient mouse. PTP1B deficient mice display an insulin sensitive
phenotype and are able to maintain glucose homeostasis with about half the
level of circulating insulin. In response to insulin administration PTP1B
deficient mice have a significant increase in insulin receptor phosphorylation
in liver and muscle compared to wild type controls. Unexpectedly these animals
were also resistant to diet induced obesity. These observations strongly
support PTP1B as a negative regulator of insulin action, thereby making it an
ideal therapeutic target for intervention in type 2 diabetes and obesity.
[Back to top] Inhibitors
of Protein Tyrosine Phosphatase 1B (PTP1B)
Scott D. Taylor
Recent studies have demonstrated
that protein tyrosine phosphatase 1B (PTP1B) is involved in the down regulation
of insulin signaling. Selective inhibitors of PTP1B hold much promise for the
treatment of type 2 diabetes mellitus and obesity. Consequently much effort, by
both industry and academia, has been devoted towards the development of PTP1B specific
inhibitors. This article gives an overview of reports that have appeared in the
primary scientific literature on the development of PTP1B inhibitors, starting
from the days of early development up to September of 2002.
[Back to top] CD45 Regulated
Signaling Pathways
Junko Irie-Sasaki , Takehiko Sasaki and Josef M. Penninger
CD45 is expressed on all
nucleated haematopoietic cells and was originally identified as the first and
prototypic transmembrane protein tyrosine phosphatase (PTPase). CD45 has been
extensively studied for over two decades as a PTPase that functions in antigen
receptor signaling by dephosphorylation of Srckinases. CD45 can operate as a
positive as well negative regulator of Src-family kinases. In CD45 mutant cell
lines, CD45-deficient mice, and CD45-deficient human SCID patients, CD45 is
required for signal transduction through antigen receptors. Our group has
recently shown that CD45 can also function as a Janus kinase (JAK) tyrosine
phosphatase that negatively regulates cytokine receptor signaling involved in
the differentiation, proliferation, and antiviral immunity of haematopoietic
cells. Moreover, a point mutation in CD45, implicated in affecting CD45
dimerization, and a genetic polymorphism that affects alternative CD45 splicing
have been implicated in autoimmunity in mice and humans. CD45 is expressed in
multiple isoforms and modulation of specific CD45 splice variants with
antibodies can prevent transplant rejections. Moreover, loss of CD45 can affect
microglia activation in a mouse model for Alzheimer’s disease. Modulation of
CD45 splice variants and CD45 activity might provide a unique opportunity to
design drugs that turn off or turn-on antigen and cytokine receptor signaling
in cancer, allergy, transplantation, or autoimmunity.
[Back to top] CD45
Protein-Tyrosine Phosphatase Inhibitor Development
Kyeong Lee and Terrence R. Burke, Jr.
The protein-tyrosine phosphatase (PTP)
CD45 serves both positive and negative signaling elements by dephosphorylating
regulatory pTyr residues on Srcfamily protein-tyrosine kinases. Although its
physiological participation in immune function makes it an important point of
intervention for treatment of a variety of inflammatory and immune disorders,
comparatively little has been reported on development of CD45 inhibitors.
Frequently, when inhibitory data against CD45 is reported, the data has been
generated secondarily to other target PTPs. The focus of the current review is
to summarize the types of structures that have been found to inhibit CD45, even
in cases the compounds themselves were designed as antagonists of other PTPs.
The review’s organization begins with generic broad spectrum PTP inhibitors and
progresses from peptide-based inhibitors and small molecule peptide mimetics to
inhibitors that have resulted from screening hits. Although potent and
moderately selective CD45 inhibitors have been reported, no single dominant
theme has yet emerged in the design of these CD45-directed agents.
[Back to top] The Leukocyte
Common Antigen-Related Protein LAR: Candidate PTP for Inhibitory Targeting
Charles M. LeVea and Robert A. Mooney
The leukocyte common antigen-related
protein, LAR, is a receptor-like protein tyrosine phosphatase (PTP) which has a
wide tissue distribution. Post-translational processing cleaves the proprotein
into two non-covalently associated subunits, an extracellular subunit
resembling a cell adhesion molecule with three immunoglobulinlike domains and
eight fibronectin III-like domains, and a phosphatase subunit containing a
short extracellular domain, a transmembrane segment, and tandem cytoplasmic PTP
catalytic domains. Current evidence supports a role for LAR in cadherin
complexes where it associates with and dephosphorylates b-catenin, a pathway which may be critical for cadherin complex
stability and cell-cell association. LAR also localizes to focal adhesions.
Evidence strongly suggests that LAR is involved in axon guidance in the
developing nervous system, being localized through association with a-liprins. Finally, considerable data support
a role for LAR in negatively regulating the insulin receptor signaling. Now
that targeting of specific PTPs for therapeutic inhibition is a reality, the
clinically relevant pathways requiring LAR must be identified. Inhibition of
LAR might improve insulin sensitivity in patients with insulin resistance and
type 2 diabetes. Unfortunately, the LAR knockout mouse displays no improvement
in insulin sensitivity but rather has defects in terminal mammary gland
development and in basal forebrain cholinergic neurons. With LAR being
implicated in diverse pathways, additional investigations are needed before clinical
targets for therapeutic inhibition of LAR can be predicted. However, selective
inhibitors of LAR would be valuable reagents to probe the function of LAR,
particularly in animal studies where the most susceptible LAR-dependent
pathway(s) must be determined.
[Back to top] Protein Tyrosine
Phosphatase α (PTPα): A Src Family Kinase Activator and Mediator of Multiple Biological Effects
Catherine J. Pallen
This review discusses progress made
over the past 10+ years in elucidating the properties, regulation, and function
of protein tyrosine phosphatase alpha (PTPa).
It is apparent from studies in knockout mice and diverse cell lines that the
major action of PTPa is as a positive
regulator of src and src family kinases. PTPa
dephosphorylates and activates src. In this manner it affects transformation
and tumourigenesis, inhibition of proliferation and cell cycle arrest, mitotic
activation of src, integrin signaling, neuronal differentiation and outgrowth,
and ion channel activity. PTPa may well
modulate additional processes, including insulin signaling, and have other
targets besides src family kinases. As an important modulator of several
specific cell signaling pathways, PTPa
has promise as a target for drug discovery. Continued research on the
physiological and pathological activities of PTPa
is necessary to define the therapeutic potential of PTPa-directed pharmacologicals.