Thyroid stimulating hormone (TSH) signaling (Homo sapiens)

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Human thyroid stimulating hormone (TSH) is a glycoprotein secreted by the anterior part of the pituitary gland (1). TSH plays an important physiological role in the regulation of the hypothalamic-pituitary-thyroid axis by modulating the release of the thyroid hormones from the thyroid gland. TSH is mainly expressed in adenohypophysis , thyroid gland, leukocyte, pituitary gland, stratum basale, stratum corneum, stratum granulosum, stratum spinosum and keratinocyte (2-4). Impairment of TSH signal transduction pathway leads to thyroid disorders such as goitre, hypothyroidism and hyperthyroidism, with complex clinical manifestations.

TSH is a heterodimer with one alpha and one beta subunit associated non-covalently. The binding of TSHB to TSHR triggers conformational changes that are transmitted through the intracellular receptor domains to promote coupling between the receptor and its cognate heterotrimeric G proteins. The TSHR activation stimulates the catalytic exchange of GDP for GTP on the Ga subunit and subsequently induces the dissociation of the GTP-bound Ga subunit from the Gß? subunit heterodimer. TSHR is reported to interact with GNA12, GNA13, GNAQ, GNAO1, GNAI2, GNAI1, GNAI3, GNAS and GNA11 G-protein subunits (5). Once dissociated, free Ga-GTP and Gß? subunits regulate the activity of enzymatic effectors, such as adenylate cyclases to generate cAMP (6, 7). cAMP activate Rap1A (Ras-Related Protein-1A) and Rap1B (Ras-Related Protein Rap1B) (8, 9). cAMP productions leads to the activation of PKA by the dissociation of regulatory subunits. Activated PKA phosphorylates its target proteins. One of the PKA substrate is the nuclear transcription factor CREB, which activates the transcription of cAMP-responsive genes after upon phosphorylation by PKA (10, 11).

TSHR also mediates its effects through Janus Kinases and Ras effectors. JAK kinases phosphorylate and activate STAT transcription factor, particularly STAT1 and STAT3 (12, 13, 14)¬¬¬¬. RAS is a guanine nucleotide-binding protein that is a key intermediate in signal transduction pathways. The RAS activation, followed by BRAF recruitment leads to the activation of the MAP kinases (ERK1/2). ERKs, once activated, translocates to the nucleus to phosphorylate several nuclear targets. In addition to JAK/STAT and Ras/MAP kinase pathways, TSH also activates PI3K (Phosphoinositide-3 Kinase). A major downstream target of PI3K pathway is the serine/threonine Kinase AKT that is involved in mediating stimulation of cell proliferation by inhibiting apoptosis (15, 16). AKT and MTOR raptor complex phosphorylation leads to activation of downstream signaling.

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