G13-dependent activation of MAPK by thyrotropin

Area of Science:

• Endocrinology
• Molecular Cell Biology
• Signal Transduction

Background:

• Thyrotropin receptor (TSHR) stimulation is known to activate G-alpha-s (G(s)) proteins, leading to cyclic AMP (cAMP) production.
• However, TSHR also activates other G protein subfamilies (G(i/o), G(q/11), and G(12/13)), with their downstream signaling pathways remaining less understood.

Purpose of the Study:

• To investigate the cAMP-independent signaling pathways activated by TSHR stimulation.
• To identify the specific G protein subfamilies involved in TSH-elicited mitogen-activated protein kinase (MAPK) activation.

Main Methods:

• Utilized human follicular thyroid carcinoma cells and primary human thyrocytes expressing TSHR.
• Employed dominant-negative constructs and shRNA to suppress G(12) and G(13) signaling.
• Investigated the role of epidermal growth factor receptor (EGFR) and Rho proteins using inhibitors and bacterial toxins.

Main Results:

• TSH stimulation induced p44/42 MAPK activation and c-Fos expression independently of G(s), G(i/o), and G(q/11).
• MAPK activation was dependent on G(13) signaling, but not G(12).
• G(13)-dependent EGFR transactivation was required for MAPK activation in carcinoma cells, but not in primary thyrocytes. Rho proteins were not involved, but Cdc42/Rac may play a role.

Conclusions:

• TSHR signaling involves a novel G(13)-dependent pathway activating p44/42 MAPK.
• This pathway is distinct from canonical cAMP signaling and involves EGFR transactivation in specific cellular contexts.
• Identifies the first G(13)-dependent TSHR signaling pathway in human thyrocytes, offering new insights into thyroid cell regulation.