0013.7227/96/$03.00/O
Endocrinolo~
Copyright
0 1996 by The Endocrine
Editorial:
Copernicus
Vol.
Printed
137, No. 7
rn U.S A.
Society
Insulin
Signaling
Network-Waiting
Not so long ago, our knowledge
of the mechanism of
insulin action was limited to a single concept that insulin via
interactions with its cell surface receptor regulates carbohydrate, lipid, and protein metabolism in insulin target cells (1).
A tide of new information crushed this simplistic model with
waves of discoveries.
Identification of the tyrosine kinase domain of the insulin
receptor (2) was followed by an isolation of the insulinreceptor substrate-l (IRS-l) and by findings that She, phosphatidylinositol
3 kinase (PI3K), growth factor receptorbound protein (Grb)-2, son of sevenless (SOS), Syp, p21Ras,
Raf-1, mitogen-activated/extracellular
response
kinase
(MEK), mitogen-activated
protein (MAP), and S6 kinases
actively participate in the transduction of insulin signaling
(reviewed in Ref. 3). In the minds of many, the crucial discovery of the mechanism of the metabolic action of insulin
was within reach, just around the corner (so to speak). Soon,
however, it became apparent that other growth factors activate the same signaling intermediates
(frequently
to a
greater degree than insulin), but they do not mimic the metabolic aspects of insulin action (3). Thus far, only activation
of PI3K has been linked to the mechanism of the insulininduced glucose transport (4). But even in this case, when
PI3K is activated by growth factors other than insulin [i.e.
platelet-derived growth factor (PDGF)], there is no concomitant increase in glucose uptake. Clearly, the mechanism of
the metabolic action of insulin still remains obscure, “just
around the corner,” where it hasbeen for the last lo-15 years.
Nevertheless, as investigators continue to navigate through
the alphabet soup of the signaling intermediates, they uncover
new and important elementsof the complex insulin signaling
network. There are several approachescommonly used to decipher the secretsof the insulin signaling: transfection of the
dominant negative or constitutively active mutants of signaling
intermediates, microinjection of specific antibodies or fusion
proteins to block activities of certain molecules, and coimmunoprecipitation to determine physical coupling of proteins. Utilizing someof these techniques, Zhang-Sun et al. (5) report in
this issueof Endocrinology several new findings about Syp, an
interesting protein-tyrosine phosphataseinvolved in the insulin
signaling network.
Syp, a nontransmembrane protein-tyrosine phosphatase,
[also known as SH-phosphotyrosine phosphatase (PTP)2,
PTPID, PTP2C, SH-PTP3, and SAP-21 is a 65-kDa protein
containing two SH2 domains (reviewed in Ref. 6). These SH2
domains are critical for Syp interactions with tyrosyl-phosphorylated proteins (7, 8). What distinguishes Syp from
many other phosphatasesis that it acts asa positive signaling
Received
April 10, 1996.
Address all correspondence
and requests for reprints
to: Boris Draznin, M.D., Ph.D., Department
of Veterans
Affairs Medical
Center, Section of Endocrinology
(lllH),
1055 Clermont
Street, Denver,
Colorado
80220. E-mail: [email protected].
2647
for
molecule in propagating the signal downstream (9-13).
Thus, expression of its catalytically inactive mutant or microinjection of Syp antibodies or Syp glutathion S-transferase
(GST)-SH2 fusion proteins results in abrogation of insulin
signaling to p21Ras, MAP kinase, and DNA synthesis (lo12). Recently, it hasbeen proposed that in addition to its other
functions, Syp may serve as an adaptor protein connecting
IRS-l with the insulin receptor (14).
Syp has been previously shown to associate with the insulin receptor, PDGF receptor, epidermal growth factor
(EGF) receptor, and IRS-l (7-9,15-17). Association with the
PDGF and EGF receptors, but not with the insulin receptor
or IRS-l, leads to phosphorylation of Syp. Thus, Syp was
believed to be activated by dual mechanisms: phosphorylation (in casesof PDGF and EGF receptors) or localization (in
case of binding to IRS-l or the insulin receptor). Zhang-Sun
and colleagues (5) have now demonstrated that, at least in the
rat hepatoma cells overexpressing insulin receptor (HTC-IR),
Syp is also being phosphorylated in response to insulin.
The second salient feature of this study is that 85% of the
cellular Syp was associated with a 60-kDa protein that was
also tyrosyl phosphorylated in response to insulin. Moreover, this p60 protein coimmunoprecipitated not only with
Syp but also with ~85 and Grb-2. This protein appears to be
distinct from the p60-GTPase-activating-protein (GAP)associated protein that binds GAP, ~85, and phospholipase
C (PLC)y (18,19). The role of the new Syp-associated p60 is
unknown and may or may not be critical for the mechanism
of Syp’s action. What is important, however, is the apparent
tissue specificity of the associations reported by Zhang-Sun
et al. The authors found an association of p60 with Syp, ~85,
and Grb-2 only in HTC-IR cells and rat adipocytes, but not
in rat liver or muscle.
As acquisition of knowledge forges ahead, recognition of the
tissue-specificinteractions among signaling intermediates assumes greater importance. Recently, we have demonstrated
that in 3T3-Ll adipocytes, but not in 3T3-Ll fibroblasts, Rat-l
fibroblasts or CHO-IR cells, PI-3 kinase appearsto exert a constitutive inhibitory influence on GAP (20). Removal of this inhibitory influence significantly increasedGAP activity and interfered with the insulin’s ability to enhance p21RasuGTP
loading. Thus, while discovering new signaling intermediates
and/or new modesof their interactions, one hasto bear in mind
that the insulin signaling network may function differently in
the “metabolically responsive” tissuesthan in the “mitogenitally responsive” cells.
Finally, if one would attempt to determine which of the
signaling intermediates occupies the central position in the
insulin signaling network (based solely on associations),one
would have to wait for the second coming of Nicolas Copernicus to solve the puzzle (Fig. 1). For now, the basic
premise of science remains unshaken: acquisition of new
knowledge generates new and more challenging questions.
2648
EDITORIAL
Endo.
Vol 137.
Alphabet
IGF-1-R
h-R
EGF-R
/
-
IRS-I
-
Crk
\
P85
p2lRa.3
I
EGF-R
P85
-
IRS-’
SYP
Cirb2
0
/
\
0
FIG. 1. Associations
among various
insulin signaling
molecules:
~85, a regulatory subunit
ofPIkinase, appears to
bind all intermediates
and tyrosine
kinase-containing
receptors.
Whether
or
not its position
in the “insulin’s
universe” is indeed central,
remains
to be
established.
molecules
h-R
\
Nck
soup of signaling
1996
No 7
p60-GAP-arsa:
0
~85
p2lRas
I
Raf
Exploration of the mechanism of insulin action has been the
best example of this rule.
Boris Draznin, M.D., Ph.D.
Department of Veterans Affairs Medical Center
Universit of Colorado Health SciencesCenter
Denver, Polorado 80220
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