Dual functions of Rack1 in regulating Hedgehog pathway

Jinxiao Liu,Xiaohan Sun,Zizhang Zhou,Dongqing Gao,Jun Luo,Qingxin Liu,Yan Ding,Yan Li,Junzheng Zhang,Jiong Chen

doi:10.1038/s41418-020-0563-7

Abstract

Hedgehog (Hh) pathway plays multiple roles in many physiological processes and its dysregulation leads to congenital disorders and cancers. Hh regulates the cellular localization of Smoothened (Smo) and the stability of Cubitus interruptus (Ci) to fine-tune the signal outputs. However, the underlying mechanisms are still unclear. Here, we show that the scaffold protein Rack1 plays dual roles in Hh signaling. In the absence of Hh, Rack1 promotes Ci and Cos2 to form a Ci–Rack1–Cos2 complex, culminating in Slimb-mediated Ci proteolysis. In the presence of Hh, Rack1 dissociates from Ci–Rack1–Cos2 complex and forms a trimeric complex with Smo and Usp8, leading to Smo deubiquitination and cell surface accumulation. Furthermore, we find the regulation of Rack1 on Hh pathway is conserved from Drosophila to mammalian cells. Our findings demonstrate that Rack1 plays dual roles during Hh signal transduction and provide Rack1 as a potential drug target for Hh-related diseases.

Highlights

The evolutionarily conserved Hedgehog (Hh) pathway is first discovered in Drosophila through EMS-induced screening [1]
We have discovered that the scaffold protein Rack1 plays dual roles in Hh signaling transduction
In the presence of Hh, Hh dissociates Cubitus interruptus (Ci)–Rack1 interaction, and promotes Rack1 forming a trimeric complex with Usp8 and Smo, resulting in Smo deubiquitination and cell surface accumulation (Fig. 7h)

Summary

Introduction

The evolutionarily conserved Hedgehog (Hh) pathway is first discovered in Drosophila through EMS-induced screening [1]. Another key component of Hh pathway is Smo, a GPCRlike transmembrane protein. With Hh stimulation, Rack dissociated from Ci–Cos complex and formed a trimeric complex with Smo and Usp, leading to Smo deubiquitination and cell surface accumulation. These results revealed that Rack plays dual roles in coordinating Hh pathway activity. Our study demonstrated that the Rack plays dual roles in Hh pathway, and provided Rack as a prudent drug target for Hh-related cancers

Results

Discussion

Methods and materials

Compliance with ethical standards