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 Müller 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 Müller 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.
Highlights
Receptor tyrosine kinases are widely expressed in the developing nervous system, where they play important roles in development of neurons and glia [1]
Receptor tyrosine kinases were initially identified as homologs of retroviral oncogene products [8]; it is not surprising that mutations in proto-oncogenes that result in constitutive activation of normal receptor tyrosine kinases render these proteins oncogenic
The erbB2/c-neu/HER2 gene is overexpressed in certain human glioblastomas [12], while the epidermal growth factor receptor gene, c-erbB, is amplified to various degrees in human glioblastomas with the highest levels of expression correlating with poor prognosis [13]
Summary
Receptor tyrosine kinases are widely expressed in the developing nervous system, where they play important roles in development of neurons and glia [1]. Receptor tyrosine kinases were initially identified as homologs of retroviral oncogene products [8]; it is not surprising that mutations in proto-oncogenes that result in constitutive activation of normal receptor tyrosine kinases render these proteins oncogenic Such activating mutations can occur within the coding region of the extracellular domain, for example in the retroviral oncogene v-erbB [8] and trk/nerve growth factor receptor gene [9]. The mutation can be an amino acid substitution in the transmembrane region, as shown for the erbB/c-neu/HER2 gene in chemically induced rat glioblastomas [10] Another means by which a receptor tyrosine kinase can become constitutively activated is by overexpression, which may result in forced receptor dimerization within the plasma membrane [11]. At least one receptor tyrosine kinase, the basic fibroblast growth factor receptor, is up-regulated in Muller glia that have
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