Fernandes H, Cohen S, Bishayee S
Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07103, USA.
J Biol Chem. 2001 Feb 16;276(7):5375-83. doi: 10.1074/jbc.M005599200. Epub 2000 Nov 21.
The epidermal growth factor receptor (EGFR) is a multisited and multifunctional transmembrane glycoprotein with intrinsic tyrosine kinase activity. Upon ligand binding, the monomeric receptor undergoes dimerization resulting in kinase activation. The consequences of kinase stimulation are the phosphorylation of its own tyrosine residues (autophosphorylation) followed by association with and activation of signal transducers. Deregulation of signaling resulting from aberrant expression of the EGFR has been implicated in a number of neoplasms including breast, brain, and skin tumors. A mutant epidermal growth factor (EGF) receptor missing 267 amino acids from the exoplasmic domain is common in human glioblastomas. The truncated receptor (EGFRvIII/DeltaEGFR) lacks EGF binding activity; however, the kinase is constitutively active, and cells expressing the receptor are tumorigenic. Our studies revealed that the high kinase activity of the DeltaEGFR is due to self-dimerization, and contrary to earlier reports, the kinase activity per molecule of the dimeric DeltaEGFR is comparable to that of the EGF-stimulated wild-type receptor. Furthermore, the phosphorylation patterns of both receptors are similar as determined by interaction with a conformation-specific antibody and by phosphopeptide analysis. This eliminates the possibility that the defective down-regulation of the DeltaEGFR is due to its altered phosphorylation pattern as has been suggested previously. Interestingly, the receptor-receptor self-association is highly dependent on a conformation induced by N-linked glycosylation. We have identified four potential sites that might participate in self-dimerization; these sites are located in a domain that plays an important role in EGFR functioning.
表皮生长因子受体（EGFR）是一种具有多个位点和多种功能的跨膜糖蛋白，具有内在的酪氨酸激酶活性。在配体结合后，单体受体发生二聚化，导致激酶激活。激酶刺激的结果是其自身酪氨酸残基的磷酸化（自磷酸化），随后与信号转导子结合并激活。由EGFR异常表达导致的信号转导失调与包括乳腺癌、脑癌和皮肤肿瘤在内的多种肿瘤有关。一种在外质结构域缺失267个氨基酸的突变型表皮生长因子（EGF）受体在人类胶质母细胞瘤中很常见。截短的受体（EGFRvIII/DeltaEGFR）缺乏EGF结合活性；然而，激酶是组成型激活的，表达该受体的细胞具有致瘤性。我们的研究表明，DeltaEGFR的高激酶活性是由于自我二聚化，与早期报道相反，二聚体DeltaEGFR每分子的激酶活性与EGF刺激的野生型受体相当。此外，通过与构象特异性抗体相互作用和磷酸肽分析确定，两种受体的磷酸化模式相似。这消除了先前提出的DeltaEGFR下调缺陷是由于其磷酸化模式改变的可能性。有趣的是，受体-受体自缔合高度依赖于N-连接糖基化诱导的构象。我们已经确定了四个可能参与自我二聚化的潜在位点；这些位点位于在EGFR功能中起重要作用的结构域中。
