LRIG1 regulates cadherin‐dependent contact inhibition directing epithelial homeostasis and pre‐invasive squamous cell carcinoma development

Abstract

Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine-rich immunoglobulin repeats-1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re-expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E-cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition.

LRIG1 Extracellular Domain: Structure and Function Analysis

“…7 (continued). transcription and to direct interactions with ErbB2, ErbB3, c-Met [9], and c-Ret [12]. LRIG1 has been reported to promote cell-cell adhesion [12].…”

“…It contains 19 β-strands with 16 LRRs (numbered [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. There are 15 complete LRRs [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15], each with 23-27 residues, where 11 LRRs have the 24-residue repeat [LxxLxLxxNxLxxLxxxx(Hφ)xx(Hφ)xx, where Hφ is any hydrophobic amino acid residue]. LRR16 is only a partial repeat with a new pattern LxxLxIxSxxFx, where Ser appears to replace Asn in the consensus repeat (LxxLxLxxNxLxx).…”

“…In the last decade, LRIG1 has been reported to interact with many receptor tyrosine kinases, GDNF/c-Ret [11], E-cadherin [12], JAK/STAT [13], c-Met [14,15], and the EGFR family [7,9] signalling systems. In some cases, LRIG1 is reported to reduce receptor levels by increasing the rates of degradation [7]; in other reports, LRIG1 appears to bind directly to the receptor kinase (e.g., the EGFR) [9].…”

Inhibition of subcutaneously implanted human pituitary tumor cells in nude mice by LRIG1

“…Long-term recurrence also exists. Therefore, studies into the genes involved in invasive pituitary tumors are the basis of efficient diagnostic and treatment strategies (Lu et al, 2013).…”

The best laid schemes of airway repair

“…This alternate strategy of CCSP-expressing cell-mediated repair of the tracheal epithelium was also replicated in vitro, suggesting that contact-mediated signalling between airway basal cells and CCSP-expressing cells is required to prevent CCSP-expressing cells dedifferentiating to basal progenitor cells in homeostatic airways. The Notch and Egfr intercellular signalling pathways, or those of other surface receptors, such as cadherins, are candidates to mediate such a signal [6][7][8].…”