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CASE FILES: BIOCHEMISTRY
the receptor is a monomer and is bound on its cytoplasmic side to an inactive
protein kinase (Janus kinase 2 [JAK2]). The JAK2 protein kinase is a different
polypeptide from the receptor and the receptor itself lacks protein kinase activ-
ity. After hormone binding and dimerization, JAK2 is activated by cross-
phosphorylation. Active JAK2 phosphorylates target proteins and itself on
specific tyrosine residues to activate them, thus initiating an autocatalytic reg-
ulatory cascade.
Growth hormone also exerts important indirect effects by stimulating the
liver and other tissues to secrete IGF-1. IGF-1 stimulates the proliferation of
chondrocytes (cartilage cells) leading to bone growth. It also stimulates
myoblast proliferation, leading to increased muscle mass. The IGF-1 receptor
contains a tyrosine kinase activity in its cytoplasmic domain that is activated
autocatalytically after IGF-1 binding, triggering activation of downstream sig-
naling molecules. In this case, tyrosine kinase activity resides on the same
polypeptide as hormone-binding activity.
Normal proliferation of somatic cells requires both thyroid hormone and
growth hormone. Thyroid hormone stimulates growth hormone secretion, and
many thyroid hormone actions on the insulin-like growth factor (IGF) system
can be explained by this mechanism.
The profound physiologic role of growth hormone is revealed by conditions
resulting from either its deficiency or excess. For example, mutations in
growth hormone or its receptor lead to dwarfism. By contrast, excessive
secretion leads to giantism, if expressed before the growth plates have
closed, or acromegaly, if overproduction is initiated in the adult. Usually,
growth hormone overproduction in the adult is the result of a noncancerous
pituitary tumor. Overgrowth (thickening) of bones and connective tissues leads
to the characteristic features of acromegaly, with accompanying enlargement
of other tissues including the heart. In women, breast milk secretion may
result. Left untreated, acromegaly may lead to DI (glucose intolerance), hyper-
tension, heart failure, and sleep apnea.
C O M P R E H E N SIO N Q U E ST IO N S
[47.1] A 30-year-old female of normal weight was recently diagnosed with
type II diabetes and hypertension. Menstrual cycles were irregular. In
appearance she had unusually coarse features; a noticeable enlarge-
ment of the tongue, hands, and feet; and a deep voice. Although not
pregnant or nursing, she unexpectedly began producing breast milk
(galactorrhea). Which one of the following possibilities is most likely
to explain all of these symptoms?
A. Hyperinsulinemia and insulin resistance
B. Pituitary tumor and growth hormone overproduction
C. Testosterone overproduction
D. Ovarian cysts
E. Transforming growth factor P overproduction
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