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Single TMS Receptors
Bryant Miles
The single transmembrane segment receptors are proteins with a single transmembrane segment. The
transmembrane segment is of course a α−helix. On either side of this membrane spanning helix are
globular domains. On the extracellular side is the binding site for the hormone, on the cystolic side of the
membrane there is a catalytic domain, typically a tyrosine kinase or guanylate cyclase. For our first
example consider the human growth hormone and its receptor. The human growth hormone is a
polypeptide hormone of 217 amino acids that forms a compact structure shown below (A). The human
growth hormone receptor is a single transmembrane segment receptor. The function of this
hormone/receptor signal transduction system is typical for these 1-TMS receptors. In the absence of the
human growth hormone, the corresponding receptor exists in a monomeric state. When the growth
hormone binds to this receptor, the binding promotes dimerization of two growth receptor molecules.
One monomeric receptor binds the red portion of the human growth hormone and the other monomeric
receptor binds to the orange portion. The binding of the hormone and the dimerization are very
cooperative processes. The dimerization brings together the globular portions (JAK2, Janus kinase 2) of
the receptor on the cystolic side of the membrane.
The JAK2 domains are tyrosine kinases. Dimerization brings together the 2 JAK2 domains of the
receptor. The two tyrosine kinases cross phosphorylate each other which causes conformational changes
that activate the two kinases for other protein substrates.
After the JAK2 enzymes have been activated by cross phosphorylation, the tyrosine kinase can
phosphorylate other substrates. One important substrate is STAT5 (STAT, Signal Transducers and
Activators of Transcription). JAK2 phosphorylates a tyrosine residue near the carboxyl terminus of
STAT5. This phosphorylated tyrosine binds to a binding site of another STAT5 molecule forming a
stable dimer. The dimerized STAT has high affinity for specific binding sites on DNA which regulate
gene expression.
Other examples are the epidermal growth factor and its receptor and the platlet derived growth factor and
its receptor. The receptors of both of these hormones exist in a monomeric state until they bind their
corresponding hormone which promotes dimerization. The dimerization induces cross phosphorylation
by the receptors tyrosine kinases. The cross phosphorylation activates the tyrosine kinases to
phosphorylate other substrate molecules which coordinate cellular processes
Small G-proteins
We have discussed the heterotrimeric G proteins. Now let’s turn our attention to the small G proteins.
These are small proteins that bind guanosine nucleotides and have intrinsic GTPase activity. The small G
proteins constitute a huge superfamily of proteins which include Ras, Rho, Arf, Rab and Ran. These
small G proteins regulate a large number of cellular processes including growth, differentiation, cell
motility, cytokinesis and cellular transport. They are homologous the heterotrimer G proteins and cycle
between binding GDP and GTP. The major differences between these two classes of G proteins is that the
small G proteins are monomeric and small. The activated form of the small G proteins is the GTP-bound
form. We are going to look the small G protein Ras. Ras stimulates cell growth and differentiation.
The epidermal growth factor (EGF) and its receptor activate Ras. The binding of EGF causes the receptor
to dimerize and cross phosphorylate itself activating the receptor tyrosine kinase. An adaptor protein
called Grb-2 binds to the phosphorylated tyrosine residue of the receptor kinase. Grb-2 is one example of
large family of proteins that bind to phosphorylated tyrosine residues. The domain that binds the
phosphoryated tyrosine residues is called the Src-homology domain 2 or SH2 for short. This adaptor
protein then recruits a protein called Sos which interacts with Grb-2. The bound Sos then binds inactive
Ras which has GDP tightly bound. The binding of Ras to the Sos-Grb-2-receptor complex causes the
guanosine nucleotide binding site to open up releasing GDP and binding GTP. For this reason, Sos is
called the guanosine nucleotide exhange factor (GEF). When Ras has GTP bound it is active and
dissociates from the complex. Ras like Gα proteins has an intrinsic GTPase activity which functions like
a timer terminating the signal, returning Ras to its inactive state.
The signaling pathway downstream of Ras activation is
shown to the left. A cascade of phosphorylations activate a
number of protein kinases which regulate many cellular
functions. Ras with GTP bound activates Raf kinase which
then activates MEK, MAP kinase kinase, which activates
MAP kinase, MAPK. MAPK migrates from the cytosol to
the nucleus where it phosphorylates transcription factors that
induce the transcription of specific genes.
Oncogenes
Oncogenes are genes that have the potential to cause a
normal cell to become cancerous.
Cell growth and differentiation are tightly controlled
processes. Tumor cells are uncontrollable rapidly
proliferating cells which can grow in invasive manner and
threaten life. Cancer is responsible for 20% of all deaths
each year.
Recently viruses that carry oncogenes that induce tumors
have been discovered. Rous Sarcoma Virus (RSV) induces
the formation of sarcomas in chickens. The gene responsible
for the sarcomas is v-src. The viral gene v-src is homologous
to a chicken gene, c-src. Both v-src and c-src encode a
tyrosine kinase. The c-src tyrosine kinase is strictly regulated while the v-src is completely unregulated.
The v-src tyrosine knase causes uncontrolled cellular proliferation producing the sarcoma.
Insulin Receptor
The most familiar 1-TMS receptor is the insulin receptor.
Insulin is the polypeptide hormone that signals a high blood
glucose concentration. Insulin promotes the transport of
glucose into the liver, muscle and adipose tissue. Insulin
promotes the storage of glucose as glycogen in the liver and
the muscle. Insulin promotes converting glucose into
triacylglycerols for storage in the adipose tissue. Insulin also
promotes protein biosynthesis and glycolysis.
The insulin receptor is a dimer of two 1-TMS domains. The
dimer is held together by disulfide bonds so that even in the
absence of insulin the receptor is a dimer. The α−subunits are
completely extracellular, the β−subunits contain the α−helix
that spans the membrane. On the cytostolic side of the
membrane the β−subunits contain the tyrosine kinase
domains. When insulin binds to one or both the insulin
binding sites, the receptor undergoes conformational changes
inducing cross phosphorylation which activates the tyrosine
kinase activity for other target proteins. One of the target
proteins is the insulin receptor substrate-1, IRS-1. IRS-1
associates with other effector proteins, such as Grb-2 which
then binds Sos which then binds and activates Ras which start
a phosphorylation cascade leading to the phosphorylation of
MAPK which activates the kinase which then migrates from the cytosol to the nucleus where it
phosphorylates transcription factors regulating gene expression.