Multidisciplinary Roles of LRRFIP1/GCF2 in Human Biological Systems and Diseases.

Masato Takimoto

doi:10.3390/cells8020108

Abstract

Leucine Rich Repeat of Flightless-1 Interacting Protein 1/GC-binding factor 2 (LRRFIP1/GCF2) cDNA was cloned for a transcriptional repressor GCF2, which bound sequence-specifically to a GC-rich element of epidermal growth factor receptor (EGFR) gene and repressed its promotor. LRRFIP1/GCF2 was also cloned as a double stranded RNA (dsRNA)-binding protein to trans-activation responsive region (TAR) RNA of Human Immunodeficiency Virus-1 (HIV-1), termed as TAR RNA interacting protein (TRIP), and as a binding protein to the Leucine Rich Repeat (LRR) of Flightless-1(Fli-1), termed as Flightless-1 LRR associated protein 1 (FLAP1) and LRR domain of Flightless-1 interacting Protein 1 (LRRFIP1). Subsequent functional studies have revealed that LRRFIP1/GCF2 played multiple roles in the regulation of diverse biological systems and processes, such as in immune response to microorganisms and auto-immunity, remodeling of cytoskeletal system, signal transduction pathways, and transcriptional regulations of genes. Dysregulations of LRRFIP1/GCF2 have been implicated in the causes of several experimental and clinico-pathological states and the responses to them, such as autoimmune diseases, excitotoxicity after stroke, thrombosis formation, inflammation and obesity, the wound healing process, and in cancers. LRRFIP1/GCF2 is a bioregulator in multidisciplinary systems of the human body and its dysregulation can cause diverse human diseases.

Highlights

Leucine Rich Repeat (LRR) domain of Flightless-1 interacting Protein 1 (LRRFIP1)/GCF2 was initially discovered as a part of an artificial chimeric cDNA
As LRRFIP1/GCF2 was initially identified as a transcriptional repressor for several growth factors and their receptors, it was presumed that it played a role in inhibiting tumor growth
One exception was that LRRFIP1/GCF2 appears to function to inhibit the overgrowth of cells treated with nerve growth factor as a player in the negative feedback mechanism [19]. Another exception was that chemo-sensitivities to anti-cancer drugs, which accompanies growth effects, were affected with the level of LRRFIP1/GCF2 expression, in which some drugs worked in a way that inhibited growth in the presence of high LRRFIP1/GCF2 expression, while some induced resistance

Summary

Introduction

LRRFIP1/GCF2 was initially discovered as a part of an artificial chimeric cDNA. After a bona fide LRRFIP1/GCF2 cDNA was cloned and shown to code a transcriptional repressor, diverse roles of this molecule in multiple biological processes, such as transcriptional regulation, signal transduction, and cytoskeletal remodeling, have been revealed. Five different isoforms of human LRRFIP1/GCF2 mRNA/cDNA have been identified and they encode proteins with amino acids ranging from 349 to 808 in number [8]. LRRFIP1/GCF2 protein consists of three domains (Figure 1); an N-terminal Helix domain, a central coiled-coil domain and a C-terminal Nucleic acid binding domain. The Nucleic acid binding domain binds to DNAs and RNAs, and the middle of this domain, which is called as Lysine rich motif, is crucial for sequence-specific binding to the double-stranded GC-rich DNA (dsDNA) element and for transcriptional repression [7] It is and required for LRRFIP1/GCF2 protein to bind to dsRNA, TRIP [4].

Domain structure of Leucine

Implications for Human Disease

Conclusions