白细胞介素-3、白细胞介素-5和GM-CSF信号
中文名称
通路描述
白细胞介素-3（IL-3）、IL-5和粒细胞巨噬细胞集落刺激因子（GM-CSF）受体形成一种异二聚体受体家族，具有特定的α链，但共享一个共同的β亚基，通常称为共同β（Bc）。两个亚基都包含细胞外保守基序，属于细胞因子受体超家族。细胞内域与其他细胞因子受体相似性有限，缺乏可检测的催化基序，如酪氨酸激基序。
IL-3是CD4+ T细胞产生的20-26 kDa产物，作用于最幼稚的骨髓祖细胞。IL-3能够诱导多潜能造血干细胞、中性粒细胞、嗜酸性粒细胞、巨核细胞、巨噬细胞、淋巴样和红细胞细胞的生长和分化。IL-3已被用于支持具有多潜能祖细胞特性的小鼠细胞系增殖，包括未分化的髓系细胞和T细胞及前B细胞（Miyajima等人，1992）。IL-5是负责嗜酸性粒细胞成熟和分化的造血生长因子。它最初被定义为T细胞衍生细胞因子，触发活化的B细胞分化为产生抗体的浆细胞。它还促进从胸腺细胞产生杀伤性T细胞。IL-5诱导IL-2受体的表达（Kouro & Takatsu，2009）。GM-CSF由炎症反应部位（T淋巴细胞、组织巨噬细胞、内皮细胞、肥大细胞）的细胞产生。它刺激粒细胞和巨噬细胞祖细胞的生长和发育，刺激树突状细胞的产生和成熟。它刺激髓原细胞和单核细胞分化，与Epo协同促进红系和巨核祖细胞增殖，作为某些类型急性髓系白血病的自分泌介质，是中性粒细胞和嗜酸性粒细胞趋化剂，增强中性粒细胞和巨噬细胞活性。在稳态条件下，GM-CSF不是髓系细胞产生的必需因素，但对于肺泡巨噬细胞的正常发育是必需的，否则将发生肺泡蛋白沉着症（PAP）。越来越多的证据表明，GM-CSF在感染引起的紧急造血（主要是髓系造血）中起关键作用，包括骨髓中粒细胞和巨噬细胞的产生、维持、生存和在损伤或刺激部位的活化（Hercus等人，2009）。
所有三个受体都有α链，以较低的亲和力结合其特异性配体（de Groot等人，1998）。Bc随后与α链结合形成高亲和力受体（Geijsen等人，2001），尽管最近对GM-CSF受体的研究表明，体内受体可能是更高阶的多聚体（Hansen等人，2008）。
受体链缺乏内在激酶活性，而是与并激活信号激酶，特别是Janus激酶2（JAK2）。这些磷酸化共同β亚基，允许招募信号分子，如Shc、磷脂酰肌醇3-激酶（PI3Ks）和信号转导和转录激活因子（STATs）。Bc细胞内域有两个功能不同的基序：膜近端区域介导增殖相关基因如c-myc、pim-1和oncostatin M的表达。该区域结合多种信号转导蛋白，包括JAK2（Quelle等人，1994）、STATs、c-Src和PI3激酶（Rao和Mufson，1995）。膜远端区域对于细胞因子诱导的生长抑制是必需的，对于造血细胞的生存是必要的（Inhorn等人，1995）。该区域与信号转导蛋白如Shc（Inhorn等人，1995）和SHP相互作用，介导c-fos、c-jun、c-Raf和p70S6K的转录激活（Reddy等人，2000）。
IL-3是CD4+ T细胞产生的20-26 kDa产物，作用于最幼稚的骨髓祖细胞。IL-3能够诱导多潜能造血干细胞、中性粒细胞、嗜酸性粒细胞、巨核细胞、巨噬细胞、淋巴样和红细胞细胞的生长和分化。IL-3已被用于支持具有多潜能祖细胞特性的小鼠细胞系增殖，包括未分化的髓系细胞和T细胞及前B细胞（Miyajima等人，1992）。IL-5是负责嗜酸性粒细胞成熟和分化的造血生长因子。它最初被定义为T细胞衍生细胞因子，触发活化的B细胞分化为产生抗体的浆细胞。它还促进从胸腺细胞产生杀伤性T细胞。IL-5诱导IL-2受体的表达（Kouro & Takatsu，2009）。GM-CSF由炎症反应部位（T淋巴细胞、组织巨噬细胞、内皮细胞、肥大细胞）的细胞产生。它刺激粒细胞和巨噬细胞祖细胞的生长和发育，刺激树突状细胞的产生和成熟。它刺激髓原细胞和单核细胞分化，与Epo协同促进红系和巨核祖细胞增殖，作为某些类型急性髓系白血病的自分泌介质，是中性粒细胞和嗜酸性粒细胞趋化剂，增强中性粒细胞和巨噬细胞活性。在稳态条件下，GM-CSF不是髓系细胞产生的必需因素，但对于肺泡巨噬细胞的正常发育是必需的，否则将发生肺泡蛋白沉着症（PAP）。越来越多的证据表明，GM-CSF在感染引起的紧急造血（主要是髓系造血）中起关键作用，包括骨髓中粒细胞和巨噬细胞的产生、维持、生存和在损伤或刺激部位的活化（Hercus等人，2009）。
所有三个受体都有α链，以较低的亲和力结合其特异性配体（de Groot等人，1998）。Bc随后与α链结合形成高亲和力受体（Geijsen等人，2001），尽管最近对GM-CSF受体的研究表明，体内受体可能是更高阶的多聚体（Hansen等人，2008）。
受体链缺乏内在激酶活性，而是与并激活信号激酶，特别是Janus激酶2（JAK2）。这些磷酸化共同β亚基，允许招募信号分子，如Shc、磷脂酰肌醇3-激酶（PI3Ks）和信号转导和转录激活因子（STATs）。Bc细胞内域有两个功能不同的基序：膜近端区域介导增殖相关基因如c-myc、pim-1和oncostatin M的表达。该区域结合多种信号转导蛋白，包括JAK2（Quelle等人，1994）、STATs、c-Src和PI3激酶（Rao和Mufson，1995）。膜远端区域对于细胞因子诱导的生长抑制是必需的，对于造血细胞的生存是必要的（Inhorn等人，1995）。该区域与信号转导蛋白如Shc（Inhorn等人，1995）和SHP相互作用，介导c-fos、c-jun、c-Raf和p70S6K的转录激活（Reddy等人，2000）。
英文描述
Interleukin-3, Interleukin-5 and GM-CSF signaling The Interleukin-3 (IL-3), IL-5 and Granulocyte-macrophage colony stimulating factor (GM-CSF) receptors form a family of heterodimeric receptors that have specific alpha chains but share a common beta subunit, often referred to as the common beta (Bc). Both subunits contain extracellular conserved motifs typical of the cytokine receptor superfamily. The cytoplasmic domains have limited similarity with other cytokine receptors and lack detectable catalytic domains such as tyrosine kinase domains.
IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009).
All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008).
The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).
Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed.
IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells (Miyajima et al. 1992). IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors (Kouro & Takatsu 2009). GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult (Hercus et al. 2009).
All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor (Geijsen et al. 2001), though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor (Hansen et al. 2008).
The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2 (Quelle et al. 1994), STATs, c-Src and PI3 kinase (Rao and Mufson, 1995). The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells (Inhorn et al. 1995). This region interacts with signal-transducing proteins such as Shc (Inhorn et al. 1995) and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K (Reddy et al. 2000).
Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed.
所含基因
23 个基因