Rao V N, Reddy E S
Department of Microbiology and Immunology, Jefferson Cancer Institute, Philadelphia, Pennsylvania 19107-5541.
Cancer Res. 1993 Aug 1;53(15):3449-54.
Mitogen-activated protein kinases (MAP kinases) or meiosis-activated myelin basic protein kinase (p44mpk) are known to be activated by a mechanism involving dual phosphorylation at both tyrosine and serine/threonine in response to many extracellular stimuli. There has been considerable speculation as to whether MAP kinases are autophosphorylated and activated by an upstream protein kinase (MAP kinase kinase) or an activator of autophosphorylation or both. Here we report that the ets-related proteins elk-1 and delta elk-1 to be potential physiological substrates and activators of MAP kinases. Our results demonstrate for the first time that MAP kinase activators can also be non-kinase proteins that enhance the autophosphorylation and activation of MAP kinase. These findings could establish a general mechanism wherein specific MAP kinase activator protein(s) may function by interacting with MAP kinases ensuring a conformational change and stimulating their autophosphorylation and activation property. Our results also suggest that the amino-terminal truncated elk-1 proteins are better activators of MAP kinase than full length proteins indicating the presence of a potential negative regulatory region which may control the kinase activator function of elk-1 proteins. Our results suggest differential regulation of elk-1 and delta elk-1 proteins in fibroblasts stimulated by epidermal growth factor implicating a key role for these proteins in the signal transduction pathway. These results establish the presence of an alternative pathway for activation of MAP kinases. Thus we propose that elk-1 proteins may represent key intermediates which would transmit signals arriving at the surface of the cell from activated receptors to downstream MAP kinases in the cytoplasm to reach the transcriptional factors in the nucleus.
丝裂原活化蛋白激酶（MAP激酶）或减数分裂活化的髓鞘碱性蛋白激酶（p44mpk）已知可通过一种机制被激活，该机制涉及在酪氨酸和丝氨酸/苏氨酸处的双重磷酸化，以响应许多细胞外刺激。关于MAP激酶是否被上游蛋白激酶（MAP激酶激酶）或自磷酸化激活剂或两者自磷酸化并激活，一直存在大量推测。在这里，我们报告ets相关蛋白elk-1和δelk-1是MAP激酶的潜在生理底物和激活剂。我们的结果首次证明，MAP激酶激活剂也可以是非激酶蛋白，它们可增强MAP激酶的自磷酸化和激活。这些发现可能建立一种普遍机制，其中特定的MAP激酶激活蛋白可能通过与MAP激酶相互作用发挥作用，确保构象变化并刺激其自磷酸化和激活特性。我们的结果还表明，氨基末端截短的elk-1蛋白比全长蛋白是更好的MAP激酶激活剂，这表明存在一个潜在的负调控区域，可能控制elk-1蛋白的激酶激活功能。我们的结果表明，在表皮生长因子刺激的成纤维细胞中，elk-1和δelk-1蛋白存在差异调节，这暗示这些蛋白在信号转导途径中起关键作用。这些结果确定了MAP激酶激活的另一条途径。因此，我们提出elk-1蛋白可能代表关键中间体，它将把从活化受体到达细胞表面的信号传递到细胞质中的下游MAP激酶，以到达细胞核中的转录因子。
