Divergent signaling capacities of the long and short isoforms of the leptin receptor
Divergent signaling capacities of the long and short isoforms of the leptin receptor
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DOI：
10.1074/jbc.272.51.32686
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发表时间：
1997-12-19
影响因子：
4.8
通讯作者：
Flier, JS
中科院分区：
文献类型：
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作者：
Bjorbaek, C;Uotani, S;Flier, JS
瘦素受体包括一个具有302个胞质残基的长型(OBR1)，它被认为介导了大部分或全部的瘦素信号转导，而几个短型(OBRs)被广泛表达，其中一个(OBRs)有34个胞浆残基，被认为不是信号，而是介导瘦素的运输或清除。我们研究了这两种受体亚型在转基因细胞中介导信号的能力。作为对瘦素的反应，OBR1而不是OBRs经历了酪氨酸磷酸化，这种磷酸化通过与JAK2的共表达而得到增强。在表达受体和JAK2的细胞中，OBRs和OBR1都介导了JAK2的瘦素依赖的酪氨酸磷酸化，当Box 1基序突变时，这种作用被OBRs取消。在表达JAK2和IRS-I受体的细胞中，瘦素通过OBRs和OBR1诱导IRS-1的酪氨酸磷酸化。在表达血凝素-ERK1和受体的COS细胞中，瘦素通过OBR1增加ERK1的活性，JAK1或JAK2的共同表达增加了ERK1的活性，而OBRs增加了ERK1的活性，尽管受体的表达增加了。在稳定表达OBRs或OBR1的中国仓鼠卵巢细胞系中，瘦素刺激内源性ERK2磷酸化。当Leptin通过OBR1刺激血凝素-STAT3的酪氨酸磷酸化和c-fos荧光素酶报告质粒的诱导时，OBRs在这些检测中没有作用。综上所述，OBR1除了激活STAT通路外，还能通过JAK向IRS-1和丝裂原活化蛋白激酶传递信号。尽管OBRs比OBR1弱很多，但它能够通过JAK介导信号转导，但这些活性对体内瘦素生物学的意义尚不清楚。
Leptin receptors include a long form (OBRl) with 302 cytoplasmic residues that is presumed to mediate most or all of leptins signaling, and several short forms, including one (OBRs) that has 34 cytoplasmic residues, is widely expressed, and is presumed not to signal but to mediate transport or clearance of leptin. We studied the abilities of these two receptor isoforms to mediate signaling in transfected cells. In response to leptin, OBRl, but not OBRs, underwent tyrosine phosphorylation that was enhanced by co-expression with JAK2. In cells expressing receptors and JAK2, both OBRs and OBRl mediated leptin-dependent tyrosine phosphorylation of JAK2, and this was abolished with OBRs when the Box 1 motif was mutated. In cells expressing receptors, JAK2 and IRS-I, leptin induced tyrosine phosphorylation of IRS-1 through OBRs and OBRl. In COS cells expressing hemagglutinin-ERK1 and receptors, leptin increased ERK1 kinase activity through OBRl, with the magnitude increased by co-expression of JAK1 or JAK2, and to a lesser degree through OBRs, despite greater receptor expression. In stable Chinese hamster ovary cell lines expressing OBRs or OBRl, leptin stimulated endogenous ERK2 phosphorylation. Whereas leptin stimulated tyrosine phosphorylation of hemagglutinin-STAT3 and induction of a c-fos luciferase reporter plasmid through OBRl, OBRs was without effect in these assays. In conclusion, OBRl is capable of signaling to IRS-1 and mitogen-activated protein kinase via JAK, in addition to activating STAT pathways. Although substantially weaker than OBRl, OBRs is capable of mediating signal transduction via JAK, but these activities are of as yet unknown significance for leptin biology in vivo.