Swindle C S, Tran K T, Johnson T D, Banerjee P, Mayes A M, Griffith L, Wells A
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
J Cell Biol. 2001 Jul 23;154(2):459-68. doi: 10.1083/jcb.200103103.
Signaling through growth factor receptors controls such diverse cell functions as proliferation, migration, and differentiation. A critical question has been how the activation of these receptors is regulated. Most, if not all, of the known ligands for these receptors are soluble factors. However, as matrix components are highly tissue-specific and change during development and pathology, it has been suggested that select growth factor receptors might be stimulated by binding to matrix components. Herein, we describe a new class of ligand for the epidermal growth factor (EGF) receptor (EGFR) found within the EGF-like repeats of tenascin-C, an antiadhesive matrix component present during organogenesis, development, and wound repair. Select EGF-like repeats of tenascin-C elicited mitogenesis and EGFR autophosphorylation in an EGFR-dependent manner. Micromolar concentrations of EGF-like repeats induced EGFR autophosphorylation and activated extracellular signal-regulated, mitogen-activated protein kinase to levels comparable to those induced by subsaturating levels of known EGFR ligands. EGFR-dependent adhesion was noted when the ligands were tethered to inert beads, simulating the physiologically relevant presentation of tenascin-C as hexabrachion, and suggesting an increase in avidity similar to that seen for integrin ligands upon surface binding. Specific binding to EGFR was further established by immunofluorescence detection of EGF-like repeats bound to cells and cross-linking of EGFR with the repeats. Both of these interactions were abolished upon competition by EGF and enhanced by dimerization of the EGF-like repeat. Such low affinity behavior would be expected for a matrix-"tethered" ligand; i.e., a ligand which acts from the matrix, presented continuously to cell surface EGF receptors, because it can neither diffuse away nor be internalized and degraded. These data identify a new class of "insoluble" growth factor ligands and a novel mode of activation for growth factor receptors.
通过生长因子受体进行的信号传导控制着诸如增殖、迁移和分化等多种细胞功能。一个关键问题是这些受体的激活是如何被调节的。这些受体的已知配体中，即便不是全部，大多数都是可溶性因子。然而，由于基质成分具有高度的组织特异性，且在发育和病理过程中会发生变化，因此有人提出某些生长因子受体可能通过与基质成分结合而被激活。在此，我们描述了一类新的表皮生长因子（EGF）受体（EGFR）配体，它存在于肌腱蛋白-C的EGF样重复序列中，肌腱蛋白-C是一种在器官发生、发育和伤口修复过程中出现的抗黏附基质成分。肌腱蛋白-C的特定EGF样重复序列以EGFR依赖的方式引发有丝分裂和EGFR自身磷酸化。微摩尔浓度的EGF样重复序列可诱导EGFR自身磷酸化，并将细胞外信号调节激酶、丝裂原活化蛋白激酶激活到与已知EGFR配体亚饱和水平诱导的水平相当。当配体与惰性珠子相连时，可观察到EGFR依赖的黏附现象，这模拟了肌腱蛋白-C作为六臂体的生理相关呈现方式，并表明亲和力增加，类似于整合素配体在表面结合时的情况。通过免疫荧光检测与细胞结合的EGF样重复序列以及EGFR与这些重复序列的交联，进一步证实了与EGFR的特异性结合。这两种相互作用在EGF竞争时都会被消除，而EGF样重复序列的二聚化则会增强这种相互作用。对于基质“固定”的配体，即一种从基质起作用、持续呈现给细胞表面EGF受体的配体，预计会出现这种低亲和力行为，因为它既不能扩散离开，也不能被内化和降解。这些数据确定了一类新的“不溶性”生长因子配体以及生长因子受体激活的一种新模式。
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