Rozengurt Enrique, Guha Sushovan, Sinnett-Smith James
Department of Medicine, School of Medicine and Molecular Biology Institute, University of California, Los Angeles 90095-1786, USA.
Eur J Surg Suppl. 2002(587):23-38.
Gastrointestinal peptides including mammalian bombesin-like peptides, cholecystokinin (CCK), gastrin, and neurotensin stimulate DNA synthesis and cell proliferation in cultured cells and are implicated as growth factors in a number of fundamental processes including development, inflammation, tissue regeneration, and neoplastic transformation. These agonists bind to G protein-coupled receptors (GPCRs) that promote Galpha q-mediated activation of beta isoforms of phospholipase C to produce two second messengers: Inositol (1,4,5) trisphosphate {Ins (1, 4, 5) P3} that mobilises Ca2+ from internal stores, and diacylglycerol that activates the classic and new isoforms of the protein kinase C (PKC) family. PKCs play a critical part in transducing bombesin/gastrin releasing peptide (GRP) receptor signals into activation of protein kinase cascades. Protein kinase D (PKD), a serine/threonine protein kinase with distinct structural and enzymological properties, is activated by phosphorylation in living cells through a new PKC-dependent signal transduction pathway. GPCR agonists including bombesin/GRP induce a rapid and striking activation of PKD by PKC. These results indicate that PKD functions downstream from PKCs and identify a new phosphorylation cascade that is activated by gastrointestinal peptide agonists. The bombesin/GRP GPCR also promotes rapid Rho-dependent assembly of focal adhesions, formation of actin stress fibres and tyrosine phosphorylation of multiple cellular proteins. We identified p125 focal adhesion kinase (FAK), p130 Crk-associated substrate (CAS) and paxillin as prominent targets of gastrointestinal peptide-stimulated tyrosine phosphorylation and developed a model that envisages a G12/Rho-dependent pathway connecting GPCR activation to the tyrosine phosphorylation of these focal adhesion proteins. Separate pathways mediate gastrointestinal peptide stimulation of additional tyrosine kinase pathways including transactivation of Src and epidermal growth factor receptor (EGFR). Tyrosine phosphorylation has a critical role in gastrointestinal peptide-induced cellular migration and cooperates with Gq-stimulated events to promote mitogenesis. The growth-promoting effects of neuropeptides and the elucidation of the signalling pathways that mediate their effects assume an added importance because these agonists and their receptors are increasingly implicated in sustaining the proliferation of clinically aggressive solid tumours including those from lung, pancreas, and colon.
胃肠道肽类，包括哺乳动物的蛙皮素样肽、胆囊收缩素（CCK）、胃泌素和神经降压素，可刺激培养细胞中的DNA合成和细胞增殖，并在包括发育、炎症、组织再生和肿瘤转化在内的许多基本过程中被认为是生长因子。这些激动剂与G蛋白偶联受体（GPCRs）结合，促进Gαq介导的磷脂酶Cβ亚型的激活，产生两种第二信使：从内部储存中动员Ca2+的肌醇（1,4,5）三磷酸{Ins(1,4,5)P3}，以及激活蛋白激酶C（PKC）家族经典和新亚型的二酰基甘油。PKC在将蛙皮素/胃泌素释放肽（GRP）受体信号转导为蛋白激酶级联反应的激活中起关键作用。蛋白激酶D（PKD）是一种具有独特结构和酶学特性的丝氨酸/苏氨酸蛋白激酶，在活细胞中通过一条新的PKC依赖性信号转导途径被磷酸化激活。包括蛙皮素/GRP在内的GPCR激动剂可通过PKC诱导PKD的快速而显著的激活。这些结果表明PKD在PKC的下游发挥作用，并确定了一条由胃肠道肽激动剂激活的新的磷酸化级联反应。蛙皮素/GRP GPCR还促进粘着斑的快速Rho依赖性组装、肌动蛋白应力纤维的形成以及多种细胞蛋白的酪氨酸磷酸化。我们确定了p125粘着斑激酶（FAK）、p130 Crk相关底物（CAS）和桩蛋白是胃肠道肽刺激酪氨酸磷酸化的主要靶点，并建立了一个模型，设想一条G12/Rho依赖性途径将GPCR激活与这些粘着斑蛋白的酪氨酸磷酸化联系起来。不同的途径介导胃肠道肽对其他酪氨酸激酶途径的刺激，包括Src和表皮生长因子受体（EGFR）的反式激活。酪氨酸磷酸化在胃肠道肽诱导的细胞迁移中起关键作用，并与Gq刺激的事件协同促进有丝分裂。神经肽的促生长作用以及介导其作用的信号通路的阐明具有额外的重要性，因为这些激动剂及其受体越来越多地与维持包括肺癌、胰腺癌和结肠癌在内的临床侵袭性实体瘤的增殖有关。
