rek, a Gene Expressed in Retina and Brain, Encodes a Receptor Tyrosine Kinase of the Axl/Tyro3 Family

Abstract

Rek (retina-expressed kinase) has been identified as a putative novel receptor-type tyrosine kinase of the Axl/ Tyro3 family with a potential role in neural cell development. rek clones were isolated from a chick embryonic brain cDNA library with a DNA probe obtained by reverse transcriptase-polymerase chain reaction of mRNA from Mü ller glia-like cells cultured from chick embryonic retina. Sequence analysis indicated that Rek is a protein of 873 amino acids with an extracellular region composed of two immunoglobulin-like domains followed by two fibronectin type III domains with eight predicted N-glycosylation sites. Two consensus src homology 2 domain binding sites are present in the cytoplasmic domain, suggesting that Rek activates several signal transduction pathways. Northern analysis of rek mRNA revealed a 5.5-kilobase transcript in chick brain, retina, and kidney and in primary cultures of retinal Mü ller glia-like cells. Rek protein was identified by immunoprecipitation and immunoblotting as a 140-kDa protein expressed in the chick retina at embryonic days 6 -13, which corresponded to the major period of neuronal and glial differentiation. Transfection of rek cDNA into COS cells resulted in transient expression of a putative precursor of 106 kDa that autophosphorylated in immune complex protein kinase assays. Overexpression of rek cDNA in mouse NIH3T3 fibroblasts resulted in activation of the 140-kDa rek kinase and induction of morphologically transformed foci. These properties indicated that Rek has oncogenic potential when overexpressed, but its normal function is likely to be related to cell-cell recognition events governing the differentiation or proliferation of neural cells.

Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site

“…Both tyrosine 779 and methionine 782 are conserved in many tyrosine kinases (Hanks et al, 1988) and the corresponding Y1313 of the Met RTK is not involved in association of signaling molecules (Ponzetto et al, 1993). In contrast, Biscardi et al (1996) propose that the corresponding position in the Rek receptor, another member of the Ufo/Axl family, may function as a potential binding site for the p85 subunit of PI3-kinase, especially as a tyrosine 821-like binding site for p85 is not present in this receptor. An interesting article by Stover et al (1995) demonstrated that two tyrosines (Y891 and Y920), located in the kinase domain of the EGF receptor are tyrosine phosphorylated by src and may function as an interaction site for src and p85a, respectively.…”

“…Ufo/Axl was identi®ed as the ®rst member of a new family of receptor tyrosine kinases (RTK), comprising at least three members, each of which has several names: Ufo/Axl/Ark/Tyro7, Tyro3/Sky/Rse/Brt/Tif/Dtk/Rek and Nyk/Mer/Eyk/Tyro12 (Janssen et al, 1991;O'Bryan et al, 1991;Rescigno et al, 1991;Lai and Lemke, 1991;Lai et al, 1994;Ohashi et al, 1994;Mark et al, 1994;Fujimoto and Yamamoto, 1994;Dai et al, 1994;Crosier et al, 1994;Biscardi et al, 1996;Paul et al, 1992;Graham et al, 1994;Jia and Hanafusa, 1994). These RTKs are characterized by an unique extracellular structure, resembling neural cell adhesion molecules (i.e.…”

Gas6-mediated survival in NIH3T3 cells activates stress signalling cascade and is independent of Ras

“…The product of the growth arrest speci®c gene gas6 (Gas6) (Man®oletti et al, 1993) is a growth factor identi®ed as the ligand for Axl/Ufo tyrosine kinase receptors (RTK) (referred thereafter as Axl) (Janssen et al, 1991;O'Bryan et al, 1991;Varnum et al, 1995). Axl is a RTK de®ning a subfamily of RTK with Rse/Sky, c-Mer/Nyk and Rek (Biscardi et al, 1996;Graham et al, 1994;Ling and Kung, 1995;Mark et al, 1994). More recent studies have shown that Gas6 can similarly bind and activate Rse/Sky and Mer RTK, although with lower a nity (Chen et al, 1997;Mark et al, 1996;Nagata et al, 1996;Ohashi et al, 1995).…”

TAM Receptor Tyrosine Kinases: Biologic Functions, Signaling, and Potential Therapeutic Targeting in Human Cancer

“…Subsequent sequence analysis revealed that Dtk and Brt were alternative splice variants (Lewis et al, 1996b). The chicken ortholog was cloned in 1996 but was given the name Rek because of limited amino acid sequence identity with the mouse and human genes (66% and 68%, respectively) (Biscardi et al, 1996). While many of these names were used initially in the literature, Tyro-3, Axl, and Mer (or MerTK) have become the most commonly published and will be used exclusively throughout the remainder of this review.…”