Distinct Pathways of ERK1/2 Activation by Hydroxy-Carboxylic Acid Receptor-1

作者：Li, Guo^*; Wang, Hui-qian; Wang, Li-hui; Chen, Ru-ping; Liu, Jun-ping

来源：PLos One, 2014, 9(3): e93041.

DOI：10.1371/journal.pone.0093041

• PROTEIN-COUPLED RECEPTORS
• SIGNAL-REGULATED KINASES
• FACTOR-I RECEPTOR
• MEDIATED ACTIVATION
• GROWTH
• GAMMA
• SRC
• G(I)
• TRANSACTIVATION
• MECHANISMS

Mechanistic investigations have shown that, upon agonist activation, hydroxy-carboxylic acid receptor-1(HCA(1)) couples to a G(i) protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for HCA(1) signaling remain largely unknown. Using CHO-K1 cells stably expressing HCA(1), and L6 cells, which endogenously express rat HCA(1) receptors, we found that activation of ERK1/2 by HCA(1) was rapid, peaking at 5 min, and was significantly blocked by pertussis toxin. Furthermore, time course experiments with different kinase inhibitors demonstrated that HCA(1) induced ERK1/2 activation via the extracellular Ca2+, PKC and IGF-I receptor transactivation-dependent pathways. In addition, we observed that pretreated the cells with M119K, an inhibitor of G(beta gamma) subunit-dependent signaling, effectively attenuated the ERK1/2 activation triggered by HCA(1), suggesting a critical role for bc-subunits in HCA(1)-activated ERK1/2 phosphorylation. Furthermore, the present results also indicated that the arrestin2/3 were not required for ERK1/2 activation. In conclusion, our findings demonstrate that upon binding to agonist, HCA(1) receptors initially activate G(i), leading to dissociation of the G(beta gamma) subunit from activated G(i), and subsequently induce ERK1/2 activation via two distinct pathways: one PKC-dependent pathway and the other IGF-IR transactivation-dependent pathway. Our results provide the first in-depth evidence that defines the molecular mechanism of HCA(1)-mediated ERK1/2 activation.

• 出版日期2014-3-26
• 单位杭州师范大学