Synergistic activation of a family of phosphoinositide 3-kinase via G-protein coupled and tyrosine kinase-related receptors
Synergistic activation of a family of phosphoinositide 3-kinase via G-protein coupled and tyrosine kinase-related receptors
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DOI：
10.1016/s0009-3084(99)00020-1
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发表时间：
1999-04-01
影响因子：
3.4
通讯作者：
Ui, M
中科院分区：
文献类型：
--
作者：
Katada, T;Kurosu, H;Ui, M
磷酸肌苷3-激酶（PI 3-激酶）是参与多种受体刺激细胞反应的关键信号酶。拥有（或偶联）蛋白酪氨酸激酶的受体刺激可激活异二聚体PI 3激酶，PI 3激酶由一个含有src同源性2 （SH2）结构域的85 kda调节亚基（p85）和一个110 kda催化亚基（p110 α或p110 β）组成。因此，这种形式的PI 3激酶可以在体外被含有YMXM基序的磷酸化酪氨酸肽激活，该肽结合p85的SH2结构域。与α - β - γ -三聚体G蛋白偶联的受体也刺激一种新的p110 γ亚型的脂质激酶活性，该亚型与p85无关，因此不被酪氨酸激酶受体激活。p110 γ PI 3-激酶的激活似乎是通过G蛋白（G β - γ）的β - γ亚基介导的。此外，含有p110 β催化亚基的大鼠肝脏异二聚体PI 3-激酶被磷酸酪氨酸肽和G β - γ协同激活。在COS-7细胞中表达的重组p110 β /p85 α也观察到这种酶促特性。相比之下，在同一大鼠肝脏中，由p110 α和p85组成的另一种异二聚体PI 3-激酶，以及重组的p110 α /p85 α，没有被G β γ激活，尽管它们的活性被磷酸酪氨酸肽刺激。在完整细胞中确实观察到两种主要受体类型的刺激对PI 3-激酶的协同激活，例如分化的THP-1和CHO细胞中的趋化肽（n -甲酰基- met - leu - phe）加胰岛素（或Fc γ II）受体和大鼠脂肪细胞中的腺苷（Al）加胰岛素受体。因此，由p110 β催化和含sh2 （p85或其相关）调控亚基组成的PI 3-激酶亚型似乎在酪氨酸激酶和G蛋白偶联受体介导的两种信号转导途径之间发挥“串扰”酶的作用。
Phosphoinositide 3-kinase (PI 3-kinase) is a key signaling enzyme implicated in a variety of receptor-stimulated cell responses. Stimulation of receptors possessing (or coupling to) protein-tyrosine kinase activates heterodimeric PI 3-kinases, which consist of an 85-kDa regulatory subunit (p85) containing Src-homology 2 (SH2) domains and a 110-kDa catalytic subunit (p110 alpha or p110 beta). Thus, this form of PI 3-kinases could be activated in vitro by a phosphotyrosyl peptide containing a YMXM motif that binds to the SH2 domains of p85. Receptors coupling to alpha beta gamma-trimeric G proteins also stimulate the lipid kinase activity of a novel p110 gamma isoform, which is not associated with p85, and thereby is not activated by tyrosine kinase receptors. The activation of p110 gamma PI 3-kinase appears to be mediated through the beta gamma subunits of the G protein (G beta gamma) In addition, rat liver heterodimeric PI 3-kinases containing the p110 beta catalytic subunit are synergistically activated by the phosphotyrosyl peptide plus G beta gamma. Such enzymatic properties were also observed with a recombinant p110 beta/p85 alpha expressed in COS-7 cells. In contrast, another heterodimeric PI 3-kinase consisting of p110 alpha and p85 in the same rat liver, together with a recombinant p110 alpha/p85 alpha, was not activated by G beta gamma, though their activities were stimulated by the phosphotyrosyl peptide. Synergistic activation of PI 3-kinase by the stimulation of the two major receptor types was indeed observed in intact cells, such as chemotactic peptide (N-formyl-Met-Leu-Phe) plus insulin (or Fc gamma II) receptors in differentiated THP-1 and CHO cells and adenosine (Al) plus insulin receptors in rat adipocytes. Thus, PI 3-kinase isoforms consisting of p110 beta catalytic and SH2-containing (p85 or its related) regulatory subunits appeared to function as a 'cross-talk' enzyme between the two signal transduction pathways mediated through tyrosine kinase and G protein-coupled receptors.