MONOCLONAL-ANTIBODIES TO THE INSULIN-RECEPTOR STIMULATE THE INTRINSIC TYROSINE KINASE-ACTIVITY BY CROSS-LINKING RECEPTOR MOLECULES
MONOCLONAL-ANTIBODIES TO THE INSULIN-RECEPTOR STIMULATE THE INTRINSIC TYROSINE KINASE-ACTIVITY BY CROSS-LINKING RECEPTOR MOLECULES
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DOI：
10.1002/j.1460-2075.1987.tb02743.x
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发表时间：
1987-12-01
期刊：
影响因子：
11.4
通讯作者：
SIDDLE, K
中科院分区：
文献类型：
--
作者：
OBRIEN, RM;SOOS, MA;SIDDLE, K
研究了抗胰岛素受体单克隆抗体对增溶受体内在激酶活性的影响。针对六种不同表位的抗体刺激受体自身磷酸化和对外源底物的激酶活性。抗体的这种作用仅在窄的浓度范围内观察到，单价抗体片段无效。通过蔗糖密度梯度离心获得了抗体-受体复合物形成的证据，该复合物涉及分子间和分子内的交叉连接，尽管自磷酸化的刺激似乎优先与后者相关。胰岛素和抗体刺激自磷酸化的作用之间存在部分加和性，尽管磷酸化位点在二维肽图上显示相同。另外两个表位的抗体未能激活受体激酶，但抑制其刺激胰岛素。抗体对激酶活性的影响与其对脂肪细胞的代谢作用一致，除了一种抗体在其代谢作用中是有效的胰岛素样的，但其拮抗胰岛素对激酶活性的刺激。它的结论是，抗体激活受体的交联亚基，而不是在特定的表位反应。一些抗体激活受体的能力可能取决于受体环境以及表位的处置。
The effect of monoclonal anti-insulin receptor antibodies on the intrinsic kinase activity of solubilized receptor was investigated. Antibodies for six distinct epitopes stimulated receptor autophosphorylation and kinase activity towards exogenous substrates. This effect of antibodies was seen only within a narrow concentration range and monovalent antibody fragments were ineffective. Evidence was obtained by sucrose density-gradient centrifugation for the formation of antibody-receptor complexes which involved both inter- and intra-molecular cross-limking, although stimulation of autophosphorylation appeared to be preferentially associated with the latter. There was partial additivity between the effects of insulin and antibodies in stimulating autophosphorylation, although the sites of phosphorylation appeared identical on two-dimensional peptide maps. Antibodies for two further epitopes failed to activate receptor kinase, but inhibited its stimulation by insulin. The effects of antibodies on kinase activity paralleled their metabolic effects on adipocytes, except for one antibody which was potently insulin-like in its metabolic effects, but which antagonized insulin stimulation of kinase activity. It is concluded that antibodies activate the receptor by cross-linking subunits rather than by reacting at specific epitopes. The ability of some antibodies to activate receptor may depend on receptor environment as well as the disposition of epitopes.