The LRIG family: enigmatic regulators of growth factor receptor signaling

Abstract

The LRIG (leucine-rich repeats and immunoglobulin-like domains) family of transmembrane proteins contains three vertebrate members (LRIG1, LRIG2, LRIG3) and one member each in flies (Lambik) and worms (Sma-10). LRIGs have stepped into the spotlight as essential regulators of growth factor receptors, including receptor tyrosine and serine/threonine kinases. LRIGs have been found to both negatively (LRIG1, LRIG3) and positively (Sma-10, LRIG3) regulate growth factor receptor expression and signaling, although the precise molecular mechanisms by which LRIGs function are not yet understood. The most is known about LRIG1, which was recently demonstrated to be a tumor suppressor. Indeed, in vivo experiments reinforce the essential link between LRIG1 and repression of its targets for tissue homeostasis. LRIG1 has also been identified as a stem cell marker and regulator of stem cell quiescence in a variety of tissues, discussed within. Comparably less is known about LRIG2 and LRIG3 although studies to date suggest that their functions are largely distinct from LRIG1 and that they likely do not serve as growth/tumor suppressors. Finally, the translational applications of expressing soluble forms of LRIG1 in LRIG1-deficient tumors are being explored and hold tremendous promise.

Decreased LRIG1 in Human Ovarian Cancer Cell SKOV3 Upregulates MRP-1 and Contributes to the Chemoresistance of VP16

“…The chromosomal regions 3p14 and 1p13 are known to be frequently deleted in cancer, while 12q13 has been reported to be over-amplified in glioblastoma. 29 The three human LRIG genes, LRIG1, LRIG2, and LRIG3, encode single-pass transmembrane proteins. LRIG1 was considered to be a tumor suppressor gene in vitro and in vivo in mice with LRIG1 ablation, such as Lrig1 neo/neo and Lrig1 Cre/Cre .…”

Functional and evolutionary insights from the Ciona notochord transcriptome

“…The fourth class is an ad hoc grouping of LRIG, CRIM1 and NAV3. All three have previously been implicated in aspects of cell signaling and/or the cytoskeleton, but have not been extensively characterized (Wilkinson et al, 2003;Kinna et al, 2006;van Haren et al, 2014;Simion et al, 2014). Their conserved expression across broad phylogenetic distances makes them attractive candidates for future functional studies of their roles in notochord morphogenesis.…”

LRIG1 Extracellular Domain: Structure and Function Analysis

“…1a). 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].…”

“…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]. These results suggest that part of the action of LRIG1 on the EGFR family may be indirect [16]. At present, the broad specificity of action of LRIG1 and the reported opposing activity of LRIG3 [17] are difficult to understand.…”