A 6-year-old girl is brought to the office for evaluation of short stature. Her parents have noticed that she bears little resemblance to her 2 older siblings. The patient's mother and father are 172.5 cm (5'8") and 183 cm (6') tall, respectively. On physical examination, the patient's height is 3 standard deviations below the mean for her age. Other findings include low-set ears, a high arched palate, a webbed neck, and cubitus valgus. Chromosomal analysis reveals a 45,XO karyotype. The patient is started on a medication to improve growth and normalize her height. Which of the following intracellular pathways is stimulated by the medication used in this patient?
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This patient with a 45,XO karyotype has Turner syndrome. Individuals with this condition are typically treated with growth hormone (GH) when growth failure becomes evident, leading to normalization of height in most patients.
GH promotes growth by acting on the cell surface receptors that stimulate production of insulin-like growth factor-1 (IGF-1), primarily in the liver. One GH molecule binds to 2 receptors on the cell surface, leading to activation of Janus kinase (JAK), a nonreceptor tyrosine kinase. JAK subsequently phosphorylates several tyrosine residues in the intracellular domain of the GH receptor. These phosphorylated tyrosine residues function as docking sites for STAT (signal transducer and activator of transcription). Once STAT is recruited to the receptor, it is also phosphorylated by JAK. STAT then dimerizes and translocates to the nucleus, where it induces IGF-1 gene transcription by binding to the promoter region. Other molecules that use the JAK-STAT pathway include cytokines (eg, interferon) and hematopoietic growth factors (eg, erythropoietin, G-CSF).
(Choice A) Steroid and thyroid hormones bind to intracellular receptors. Once these receptors are activated, they subsequently bind to the promoter region of target genes to modify transcription.
(Choice B) Several hormones (eg, PTH, ACTH, TSH, ADH [V2 receptor]) activate adenylyl cyclase after binding to G protein-coupled receptors on the cell membrane. Adenylyl cyclase converts ATP to cyclic AMP, which subsequently activates protein kinase A.
(Choices C and D) Various hormones (eg, GnRH, TRH, angiotensin II, ADH [V1 receptor]) function by binding to G protein-coupled receptors that activate phospholipase C. Activated phospholipase C hydrolyzes phosphatidylinositol bisphosphate to inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 mobilizes calcium from the endoplasmic reticulum, and DAG directly activates protein kinase C.
Educational objective:
Growth hormone binds to cell surface receptors, leading to intracellular activation of the JAK-STAT pathway. Cytokines (eg, interferon) and hematopoietic growth factors (eg, erythropoietin, G-CSF) also use this pathway.