RESUMO
The Eph receptor tyrosine kinases make up an important family of signal transduction molecules that control many cellular processes, including cell adhesion and movement, cell shape, and cell growth. All of these are important aspects of cancer progression, but the relationship between Eph receptors and cancer is complex and not fully understood. Genetic screens of tumor specimens from cancer patients have revealed somatic mutations in many Eph receptors. The most highly mutated Eph receptor is EphA3, but its functional role in cancer is currently not well established. Here we show that many EphA3 mutations identified in lung, colorectal, and hepatocellular cancers, melanoma, and glioblastoma impair kinase activity or ephrin ligand binding and/or decrease the level of receptor cell surface localization. These results suggest that EphA3 has ephrin- and kinase-dependent tumor suppressing activities, which are disrupted by somatic cancer mutations.
Assuntos
Regulação Neoplásica da Expressão Gênica , Mutação , Neoplasias/genética , Receptores Proteína Tirosina Quinases/genética , Membrana Celular/metabolismo , Progressão da Doença , Efrina-A3/química , Fibronectinas/química , Células HEK293 , Humanos , Immunoblotting/métodos , Modelos Biológicos , Modelos Genéticos , Neoplasias/patologia , Conformação Proteica , Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Receptores Proteína Tirosina Quinases/metabolismo , Receptor EphA3 , Transdução de SinaisRESUMO
Ephrin ligands presented on one cell surface associate with their receptors on the surface of a juxtaposed cell, often resulting in cell-cell repulsion. In this issue of Cell, Janes et al. (2005) show that the ephrin ligand can be proteolytically released from its membrane tether by a complex on the opposing cell composed of the ephrin receptor and an ADAM metalloprotease.
Assuntos
Proteínas ADAM/metabolismo , Efrina-A2/metabolismo , Efrina-A3/metabolismo , Efrina-A5/metabolismo , Proteínas de Membrana/metabolismo , Proteínas ADAM/química , Proteínas ADAM/genética , Proteína ADAM10 , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide , Cristalografia por Raios X , Cisteína/química , Efrina-A3/química , Efrina-A5/química , Humanos , Ligantes , Proteínas de Membrana/química , Proteínas de Membrana/genética , Modelos Biológicos , Dados de Sequência Molecular , Mutagênese , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptor EphA3/metabolismo , Homologia de Sequência de Aminoácidos , Especificidade por SubstratoRESUMO
The Eph family of receptor tyrosine kinases and their ephrin ligands are mediators of cell-cell communication. Cleavage of ephrin-A2 by the ADAM10 membrane metalloprotease enables contact repulsion between Eph- and ephrin-expressing cells. How ADAM10 interacts with ephrins in a regulated manner to cleave only Eph bound ephrin molecules remains unclear. The structure of ADAM10 disintegrin and cysteine-rich domains and the functional studies presented here define an essential substrate-recognition module for functional interaction of ADAM10 with the ephrin-A5/EphA3 complex. While ADAM10 constitutively associates with EphA3, the formation of a functional EphA3/ephrin-A5 complex creates a new molecular recognition motif for the ADAM10 cysteine-rich domain that positions the proteinase domain for effective ephrin-A5 cleavage. Surprisingly, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells. Our data suggest a simple mechanism for regulating ADAM10-mediated ephrin proteolysis, which ensures that only Eph bound ephrins are recognized and cleaved.