Targeted disruption of LIG‐1 gene results in psoriasiform epidermal hyperplasia¹

Abstract

The gene encoding a transmembrane glycoprotein LIG-1, of which the extracellular region was organized with the leucine-rich repeats and immunoglobulin-like domains, was disrupted in mice by gene targeting. LIG-1-deficient mice developed a skin change on the tail and facial area after birth. The affected skin was histologically reminiscent of the epidermis in human common skin disease 'psoriasis'. LIG-1 was expressed in basal cells of the epidermis and outer root sheath cells of hair follicles in mice. Interestingly, the LIG-1 expression was apparently down-regulated in the psoriatic lesions, suggesting that LIG-1 inversely correlates with proliferative ability of epidermal keratinocytes. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Others negative regulators induced by EGFR signaling include Sprouty-2, which modulates the Ras/MAPK pathway, LRIG-1, which enhances Cbl recruitment to EGFR and EGFR ubiquitinylation, and MIG-6/RALT, which binds directly to tyrosine kinase domain αI helix of EGFR allosterically inhibiting its catalytic activity [102,103]. Consistent with its proposed role in negatively regulating EGFR, mutation of LRIG-1 (LIG-1) in mice leads to psoriasiform skin lesions consistent with the proposed role of EGFR in psoriasis [104,105]. Notably, Mig-6 mouse mutants hyperactivate EGFR, leading to MAPK stimulation and the development of benign and malignant tumors of the stomach, colon, biliary tree and lung with enhanced susceptibility to carcinogen-induced skin cancer [106,107].…”

“…Psoriasis may be driven in part by unregulated activation of EGFR consistent with its aberrant expression throughout the interfollicular epidermis of psoriatic lesions. Mouse models also support this hypothesis with thinned epidermis in mice lacking EGFR, and psoriasiform lesions in mice lacking the EGFR inhibitor LRIG-1 [104,105]. Mycobacterium leprae can bind directly to ErbB2 to activate the receptor and MAPK signaling independent of dimerization with other ErbB receptors.…”

Negative regulation of receptor tyrosine kinases: unexpected links to c-Cbl and receptor ubiquitylation

“…The extracellular regions of both the murine Lrig1/ Lig-1 [47] and the human LRIG1 [46] share 15 LRRs followed by three Ig domains. Interestingly, disruption of the LRIG1 gene in mice resulted in fertile animals that developed defects in skin [48], a major site of EGFR action.…”

LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII

“…LRIG1 opposes tumor cell proliferation, motility and invasion in vitro and has been proposed to function as a tumor suppressor (Hedman et al, 2002). Although genetic evidence of LRIG1's tumor suppressor activity is currently lacking, LRIG1 null mice develop a psoriasiform epidermal hyperplasia, consistent with a role for LRIG1 as a growth suppressor (Suzuki et al, 2002). In addition, LRIG1 is underexpressed in a number of tumor types (Thomasson et al, 2003;Tanemura et al, 2005;Lindstro¨m et al, 2008;Miller et al, under revision).…”