Nuclear translocation of IGF-1R via p150Glued and an importin-β/RanBP2-dependent pathway in cancer cells

Abstract

Mounting evidence has shown that the insulin-like growth factor-1 receptor (IGF-1R) has critical roles in cancer cell growth. This has prompted pharmacological companies to develop agents targeting the receptor. Surprisingly, clinical trials using specific IGF-1R antibodies have, however, revealed disappointing results. Further understanding of the role of IGF-1R in cancer cells is therefore necessary for development of efficient therapeutic strategies. Recently, we showed that IGF-1R is sumoylated and translocated into the cell nucleus where it activates gene transcription. Several other studies have confirmed our findings and it has been reported that nuclear IGF-1R (nIGF-1R) has prognostic and predictive impact in cancer. To increase the understanding of IGF-1R in cancer cells, we here present the first study that proposes a pathway by which IGF-1R translocates into the cell nucleus. We could demonstrate that IGF-1R first associates with the dynactin subunit p150(Glued), which transports the receptor to the nuclear pore complex, where it co-localizes with importin-β followed by association with RanBP2. Sumoylation of IGF-1R seems to be required for interaction with RanBP2, which in turn may serve as the SUMO E3 ligase. In the context of sumoylation, we provided evidence that it may favor nIGF-1R accumulation by increasing the stability of the receptor. Taken together, topographic and functional interactions between dynactin, importin-β and RanBP2 are involved in nuclear translocation of IGF-1R. Our results provide new understanding of IGF-1R in cancer, which in turn may contribute to development of new therapeutic strategies.

SUMO‐modified insulin‐like growth factor 1 receptor (IGF‐1R) increases cell cycle progression and cell proliferation

“…Recently, we showed that the IGF‐1R undergoes SUMOylation, which leads to nuclear translocation and gene activation through binding to enhancers or nuclear proteins (Packham et al, 2015; Sehat et al, 2010; Warsito, Lin, Gnirck, Sehat, & Larsson, 2016; Warsito, Sjöström, Andersson, Larsson, & Sehat, 2012). Introduction of site specific mutations corresponding to three evolutionary conserved SUMOylation sites (Lys1025, Lys1100, and Lys1120) in IGF1R decreased nuclear IGF‐1R (nIGF‐1R) and abolished its gene regulatory effects while retaining IGF‐1R kinase‐dependent signaling (Sehat et al, 2010).…”

Function of insulin‑like growth factor 1 receptor in cancer resistance to chemotherapy (Review)

“…Previous studies have revealed that IGF1R is sumoylated and translocated to the nucleus, which permits the receptor to interact with chromatin, and function as a transcriptional regulator (95)(96)(97). Nuclear IGF1R specifically binds to and functions as a transcriptional activator of its own promoter, and interferes with signaling pathways (98).…”

RANBP2 (RAN binding protein 2)

“…Miyauchi et al (2012) demonstrated a role of RANBP2 in SUMOylation and localization of MDM2, a major regulator of p53 stability, suggesting therefore a possible indirect implication of RANBP2 in p53 functions. Packham et al (2014) showed that RANBP2 is implicated in the pro-tumorigenic activity of the insulin-like growth factor-1 receptor (IGF-1R), an activator of the PI3K/Akt pathway with key roles in tumorigenesis. The biological activity of IGF-1R depends on its nuclear translocation, which in turn depends on SUMOylation.…”

“…The biological activity of IGF-1R depends on its nuclear translocation, which in turn depends on SUMOylation. Packham et al (2014) characterized spatially regulated interactions of IGF-1R, first with dynactin, which transports IGF-1R to NPCs, and therein with importin-β and RANBP2. RANBP2 interacts with and stabilizes sumoylated IGF-1R, enabling its nuclear accumulation and hence the activation of tumorigenic pathways that depend on it.…”