Protein tyrosine phosphatase non-receptor type 5 is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''PTPN5''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Protein tyrosine phosphatase (
PTP), non-receptor type 5, also known as STEP (STriatal-Enriched protein tyrosine Phosphatase), was the first brain-specific PTP discovered.
The human STEP locus maps to chromosome 11p15.2-p15.1 and the murine STEP gene to chromosome 7B3-B5. The single STEP gene is alternatively spliced to produce several isoforms, the best characterized of which are the cytosolic STEP
46 protein and the membrane-associated STEP
61 protein.
Substrates
Seven known targets of STEP have been identified as of 2015, including
ERK1/2,
,
,
Pyk2,
,
and the glutamate receptor subunits
GluN2B and
GluA2.
STEP dephosphorylation of the
kinases
In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...
(ERK1/2, p38, Fyn, and Pyk2) occurs at a regulatory
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
within the kinase activation loop and leads to their inactivation. Dephosphorylation of a regulatory tyrosine on PTPα prevents the translocation of PTPα from the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
to
lipid rafts, where it normally activates Fyn.
STEP thereby directly inactivates Fyn and also prevents the translocation of PTPα to compartments where it activates Fyn. STEP dephosphorylation of GluN2B and GluA2 leads to the internalization of
NMDARs (GluN1/GluN2B) and
AMPARs (GluA1/GluA2). Thus, one function of STEP is to oppose synaptic strengthening by inactivating kinases and internalizing receptors that are critical for the development of synaptic strengthening.
Clinical significance
STEP levels are disrupted in several diseases.
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
(AD) was the first illness to be associated with elevated STEP expression both in human cortex and in several mouse models of AD.
STEP is also increased in
fragile X syndrome
Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder. The average IQ in males with FXS is under 55, while affected females tend to be in the borderline to normal range, typically around 70–85. Physical features may include a lo ...
,
schizophrenia
Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
, and
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
. In AD and FXS mouse models, genetic reduction of STEP expression reverses many of the cognitive and behavioral deficits.
Other laboratories have now shown that STEP activity is also reduced in several additional disorders. Thus, STEP levels or activity is decreased in
Huntington's disease
Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...
,
cerebral ischemia,
alcohol abuse
Alcohol abuse encompasses a spectrum of alcohol-related substance abuse. This spectrum can range from being mild, moderate, or severe. This can look like consumption of more than 2 drinks per day on average for men, or more than 1 drink per ...
, and
stress disorders. The emergent model suggests that an optimal level of STEP is required at
synaptic sites, and that both high and low levels disrupt synaptic function.
Inhibition
Several STEP inhibitors have now been discovered.
GlaxoSmithKline
GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...
chose STEP as a new project for their Discovery Partnerships with Academia (DPAc) in 2014. This is a relatively new program in drug discovery and brings together the academic world with the drug discovery expertise of GSK to discover new inhibitors of validated targets.
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TC-2153
References
Further reading
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{{Protein tyrosine phosphatases