Katada T, Kurosu H, Okada T, Suzuki T, Tsujimoto N, Takasuga S, Kontani K, Hazeki O, Ui M
Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
Chem Phys Lipids. 1999 Apr;98(1-2):79-86. doi: 10.1016/s0009-3084(99)00020-1.
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 (A1) 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.
磷脂酰肌醇3激酶（PI 3激酶）是一种关键的信号酶，参与多种受体刺激的细胞反应。具有（或偶联至）蛋白酪氨酸激酶的受体受到刺激后会激活异二聚体PI 3激酶，该激酶由一个含有Src同源2（SH2）结构域的85 kDa调节亚基（p85）和一个110 kDa催化亚基（p110α或p110β）组成。因此，这种形式的PI 3激酶在体外可被含有与p85的SH2结构域结合的YMXM基序的磷酸酪氨酸肽激活。偶联至αβγ三聚体G蛋白的受体也会刺激一种新型p110γ同工型的脂质激酶活性，该同工型不与p85相关，因此不会被酪氨酸激酶受体激活。p110γ PI 3激酶的激活似乎是通过G蛋白的βγ亚基（Gβγ）介导的。此外，含有p110β催化亚基的大鼠肝脏异二聚体PI 3激酶会被磷酸酪氨酸肽加Gβγ协同激活。在COS - 7细胞中表达的重组p110β/p85α也观察到了这种酶活性。相比之下，同一大鼠肝脏中由p110α和p85组成的另一种异二聚体PI 3激酶，以及重组p110α/p85α，虽然其活性会被磷酸酪氨酸肽刺激，但不会被Gβγ激活。在完整细胞中确实观察到了两种主要受体类型的刺激对PI 3激酶的协同激活，例如在分化的THP - 1和CHO细胞中趋化肽（N - 甲酰 - 甲硫氨酸 - 亮氨酸 - 苯丙氨酸）加胰岛素（或FcγII）受体，以及在大鼠脂肪细胞中腺苷（A1）加胰岛素受体。因此，由p110β催化亚基和含SH2（p85或其相关）调节亚基组成的PI 3激酶同工型似乎在通过酪氨酸激酶和G蛋白偶联受体介导的两条信号转导途径之间起“串扰”酶的作用。
