Cdh1 Regulates Osteoblast Function through an APC/C-Independent Modulation of Smurf1

Abstract

Summary The APC/Cdh1 E3 ubiquitin ligase plays an essential role in both mitotic exit and G1/S transition by targeting key cell cycle regulators for destruction. There is mounting evidence indicating that Cdh1 has other functions in addition to cell cycle regulation. However, it remains unclear whether these additional functions depend on its E3 ligase activity. Here we report that Cdh1, but not Cdc20, promotes the E3 ligase activity of Smurf1. This is mediated by disruption of an auto-inhibitory Smurf1 homodimer and is independent of APC/Cdh1 E3 ligase activity. As a result, depletion of Cdh1 leads to reduced Smurf1 activity and subsequent activation of multiple downstream targets including the MEKK2 signaling pathway, inducing osteoblast differentiation. Our studies uncover a cell cycle-independent function of Cdh1, establishing Cdh1 as an upstream component that governs Smurf1 activity. They further suggest that modulation of Cdh1 is a potential therapeutic option for treatment of osteoporosis.

Cdh1 regulates craniofacial development via APC-dependent ubiquitination and activation of Goosecoid

“…During the rest of the cell cycle, Cdh1 is largely APC free [28]. Our previous study has demonstrated that APC-free Cdh1 augments Smurf1 E3 ligase activity to govern osteoblast differentiation [17]. In the present study, we identified Gsc as a new substrate of APC Cdh1 and further revealed a novel role for Cdh1 in craniofacial development through promoting APC-dependent, non-proteolytic ubiquitination and activation of Gsc. It has been well characterized previously that APC promotes substrate ubiquitination in two distinct steps by associating with two different E2-conjugating enzymes, UBCH10 and Ube2S, which leads to initial monoubiquitination and subsequent K11-linkage polyubiquitination [29].…”

“…Besides its conventional roles in cell cycle regulation, Cdh1 has recently been found to play critical roles in a wide spectrum of cellular processes including DNA damage repair [9,12], cellular metabolism [13], cell migration [14] and neuronal development [15,16]. Moreover, we recently identified a novel, APC-independent, role for Cdh1 in controlling osteoblast differentiation by disrupting the inter-molecular interaction of Smurf1 dimers, leading to the activation of Smurf1, another member of the NEDD4 family of E3 ligases [17].…”

Deubiquitinase FAM/USP9X Interacts with the E3 Ubiquitin Ligase SMURF1 Protein and Protects It from Ligase Activity-dependent Self-degradation

“…Cdh1, a subunit of the Anaphase promoting complex, was reported to bind C2 and the WW1 domain of SMURF1. Such an interaction also leads to SMURF1 activation, possibly by disrupting SMURF1 homodimer formation (49). Cerebral cavernous malformation 2 recognizes the HECT domain of SMURF1 and helps to localize SMURF1 to the plasma membrane to enhance RhoA ubiquitination and degradation (50).…”

Stk38 protein kinase preferentially inhibits TLR9-activated inflammatory responses by promoting MEKK2 ubiquitination in macrophages

“…This result suggested that each of the three domains was required for the interaction between Smurf1 and Stk38. Similarly as many other E3 ubiquitin ligases, activation of Smurf1 was dependent on ubiquitination of itself 27 . Thus, we detected the effect of Stk38 on Smurf1 ubiquitination.…”