LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor

Abstract

In baseball parlance, a triple threat is a person who can run, hit and throw with aplomb. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a cell surface protein that antagonises ERBB receptor signalling by downregulating receptor levels. Over 10 years ago, Hedman et al postulated that LRIG1 might be a tumour suppressor. Recently, Powell et al provided in vivo evidence substantiating that claim by demonstrating that Lrig1 loss in mice leads to spontaneously arising, highly penetrant intestinal adenomas. Interestingly, Lrig1 also marks stem cells in the gut, suggesting a potential role for Lrig1 in maintaining intestinal epithelial homeostasis. In this review, we will discuss the ability of LRIG1 to act as a triple threat: pan-ERBB negative regulator, intestinal stem cell marker and tumour suppressor. We will summarise studies of LRIG1 expression in human cancers and discuss possible related roles for LRIG2 and LRIG3.

Figure 1

LRIG1 negatively regulates EGFR signalling. EGFR ligand binding results in phosphorylation of ERBBs and activation of downstream receptor tyrosine kinase signalling. In the current model, LRIG1 is postulated to associate with the EGFR ectodomain and accelerate recruitment of the E3 ligase c-CBL through a CBL-binding domain in the LRIG1 cytoplasmic tail. This effectively increases EGFR ubiquitylation and lysosomal degradation, resulting in decreased receptor levels at the cell surface. LRIG1 potentially downregulates other ERBBs through direct interaction or ERBB heterodimerisation with EGFR.

Figure 2

LRIG1 expression in colorectal cancers. Box plot of the LRIG1 gene signature in the TCGA colorectal adenocarcinoma data set. LRIG1 expression is significantly downregulated in tumours compared with normal tissues. P<0.001.

Figure 3

LRIG1 expression in breast cancers. (A) Box plot of the LRIG1 gene signature in the UNC337 human breast tumour data set based on intrinsic subtypes. LRIG1 expression appears to be significantly upregulated only in the Luminal A intrinsic subtype compared with normal (P=5.83e–40). (B) When divided into high (50/128) and low (29/128) LRIG1-expression groups, patients with high LRIG1 expression exhibit longer relapse-free survival. P-values reflect statistical significance of analysis of variances (ANOVAs; P=0.00561).