催乳素受体信号
中文名称
通路描述
催乳素（PRL）主要由腺垂体分泌。它最初因其刺激乳腺发育和泌乳的能力而被发现，但现在已知具有许多多样的功能。尽管如此，与催乳素受体（PRLR）信号异常相关的病理现象很少，尽管在癌症和某些自身免疫疾病中的作用已被提出。大量文献表明 PRL 对免疫细胞有影响，但 PRLR KO 小鼠的免疫系统和发育功能未受影响。除了垂体外，许多其他组织产生 PRL，包括蜕膜和子宫肌层、免疫系统中的某些细胞、大脑、皮肤和内分泌腺（如乳腺、汗腺和泪腺）（Ben-Jonathan et al. 1996）。垂体 PRL 分泌受来自下丘脑的抑制因子负调控，其中最重要的是多巴胺，通过存在于泌乳细胞中的 D2 亚类多巴胺受体起作用（Freeman et al. 2000）。PRL 结合位点或受体已在许多成年哺乳动物的细胞和组织中被鉴定。各种形式的 PRLR 通过替代剪接在几种物种中报告，包括人类（Kelly et al. 1991, Clevenger et al. 2003）。PRLR 是细胞因子受体超家族的一员。与其他该家族许多成员一样，受体激活的第一步通常被认为是配体诱导的二聚化，即一个 PRL 分子与两个受体分子结合（Elkins et al. 2000）。最近的研究表明，PRLR 在缺乏配体时预先在细胞膜上组装（Gadd & Clevenger 2006, Tallet et al. 2011），表明配体诱导的激活涉及预先形成的 PRLR 二聚体的构象变化（Broutin et al. 2010）。PRLR 本身没有内在的激酶活性，但与 JAK2 结合（Lebrun et al. 1994, 1995），JAK2 在受体激活后激活（Campbell et al. 1994, Rui et al. 1994, Carter-Su et al. 2000, Barua et al. 2009）。据报道，JAK2 依赖的 JAK1 激活也被报道（Neilson et al. 2007）。通常认为，JAK2 的激活是通过配体诱导的受体激活后的转磷酸化发生的，基于融合有细胞因子或酪氨酸激酶受体各种细胞外域的 chimeric 受体对 JAK 激活的 JAK（见 Ihle et al. 1994）。此激活步骤涉及 JAK2 的酪氨酸磷酸化，后者磷酸化 PRLR 上的特定内酪氨酸残基，导致 STAT5 招募和信号传导，被认为是 PRLR 最重要的信号传导通路。据报道，STAT1 和 STAT3 的激活也被报道（DaSilva et al. 1996），还有许多其他信号通路；通过 MAP 激酶（Shc/SOS/Grb2/Ras/Raf/MAPK）的信号传导也被报道为许多不同细胞系统中 PRL 刺激的后果（见 Bole-Feysot et al. 1998），尽管不清楚该信号如何传播。其他非穷尽的级联包括 Src 激酶、 focal 粘附激酶、磷脂酶 C gamma、PI3 激酶/Akt 和 Nek3（Clevenger et al. 2003, Miller et al. 2007）。蛋白酪氨酸磷酸酶 SHP2 被招募到 PRLR 的 C 末端酪氨酸，可能具有调节作用（Ali & Ali 2000）。PRLR 磷酸酪氨酸可招募胰岛素受体底物（IRS）和其他适配蛋白到受体复合物（Bole-Feysot et al. 1998）。雌性纯合 PRLR 敲除小鼠完全不育且缺乏乳腺发育（Ormandy et al. 1997）。半合子无法在第一次怀孕后泌乳，并且根据遗传背景，这种表型可能持续通过随后的怀孕（Kelly et al. 2001）。
英文描述
Prolactin receptor signaling Prolactin (PRL) is a hormone secreted mainly by the anterior pituitary gland. It was originally identified by its ability to stimulate the development of the mammary gland and lactation, but is now known to have numerous and varied functions (Bole-Feysot et al. 1998). Despite this, few pathologies have been associated with abnormalities in prolactin receptor (PRLR) signaling, though roles in various forms of cancer and certain autoimmune disorders have been suggested (Goffin et al. 2002). A vast body of literature suggests effects of PRL in immune cells (Matera 1996) but PRLR KO mice have unaltered immune system development and function (Bouchard et al. 1999). In addition to the pituitary, numerous other tissues produce PRL, including the decidua and myometrium, certain cells of the immune system, brain, skin and exocrine glands such as the mammary, sweat and lacrimal glands (Ben-Jonathan et al. 1996). Pituitary PRL secretion is negatively regulated by inhibitory factors originating from the hypothalamus, the most important of which is dopamine, acting through the D2 subclass of dopamine receptors present in lactotrophs (Freeman et al. 2000). PRL-binding sites or receptors have been identified in numerous cells and tissues of adult mammals. Various forms of PRLR, generated by alternative splicing, have been reported in several species including humans (Kelly et al. 1991, Clevenger et al. 2003).
PRLR is a member of the cytokine receptor superfamily. Like many other members of this family, the first step in receptor activation was generally believed to be ligand-induced dimerization whereby one molecule of PRL bound to two molecules of receptor (Elkins et al. 2000). Recent reports suggest that PRLR pre-assembles at the plasma membrane in the absence of ligand (Gadd & Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in preformed PRLR dimers (Broutin et al. 2010).
PRLR has no intrinsic kinase activity but associates (Lebrun et al. 1994, 1995) with Janus kinase 2 (JAK2) which is activated following receptor activation (Campbell et al. 1994, Rui et al. 1994, Carter-Su et al. 2000, Barua et al. 2009). JAK2-dependent activation of JAK1 has also been reported (Neilson et al. 2007). It is generally accepted that activation of JAK2 occurs by transphosphorylation upon ligand-induced receptor activation, based on JAK activation by chimeric receptors in which various extracellular domains of cytokine or tyrosine kinase receptors were fused to the IL-2 receptor beta chain (see Ihle et al. 1994). This activation step involves the tyrosine phosphorylation of JAK2, which in turn phosphorylates PRLR on specific intracellular tyrosine residues leading to STAT5 recruitment and signaling, considered to be the most important signaling cascade for PRLR. STAT1 and STAT3 activation have also been reported (DaSilva et al. 1996) as have many other signaling pathways; signaling through MAP kinases (Shc/SOS/Grb2/Ras/Raf/MAPK) has been reported as a consequence of PRL stimuilation in many different cellular systems (see Bole-Feysot et al. 1998) though it is not clear how this signal is propagated. Other cascades non exhaustively include Src kinases, Focal adhesion kinase, phospholipase C gamma, PI3 kinase/Akt and Nek3 (Clevenger et al. 2003, Miller et al. 2007). The protein tyrosine phosphatase SHP2 is recruited to the C terminal tyrosine of PRLR and may have a regulatory role (Ali & Ali 2000). PRLR phosphotyrosines can recruit insulin receptor substrates (IRS) and other adaptor proteins to the receptor complex (Bole-Feysot et al. 1998).
Female homozygous PRLR knockout mice are completely infertile and show a lack of mammary development (Ormandy et al. 1997). Hemizogotes are unable to lactate following their first pregnancy and depending on the genetic background, this phenotype can persist through subsequent pregnancies (Kelly et al. 2001).
PRLR is a member of the cytokine receptor superfamily. Like many other members of this family, the first step in receptor activation was generally believed to be ligand-induced dimerization whereby one molecule of PRL bound to two molecules of receptor (Elkins et al. 2000). Recent reports suggest that PRLR pre-assembles at the plasma membrane in the absence of ligand (Gadd & Clevenger 2006, Tallet et al. 2011), suggesting that ligand-induced activation involves conformational changes in preformed PRLR dimers (Broutin et al. 2010).
PRLR has no intrinsic kinase activity but associates (Lebrun et al. 1994, 1995) with Janus kinase 2 (JAK2) which is activated following receptor activation (Campbell et al. 1994, Rui et al. 1994, Carter-Su et al. 2000, Barua et al. 2009). JAK2-dependent activation of JAK1 has also been reported (Neilson et al. 2007). It is generally accepted that activation of JAK2 occurs by transphosphorylation upon ligand-induced receptor activation, based on JAK activation by chimeric receptors in which various extracellular domains of cytokine or tyrosine kinase receptors were fused to the IL-2 receptor beta chain (see Ihle et al. 1994). This activation step involves the tyrosine phosphorylation of JAK2, which in turn phosphorylates PRLR on specific intracellular tyrosine residues leading to STAT5 recruitment and signaling, considered to be the most important signaling cascade for PRLR. STAT1 and STAT3 activation have also been reported (DaSilva et al. 1996) as have many other signaling pathways; signaling through MAP kinases (Shc/SOS/Grb2/Ras/Raf/MAPK) has been reported as a consequence of PRL stimuilation in many different cellular systems (see Bole-Feysot et al. 1998) though it is not clear how this signal is propagated. Other cascades non exhaustively include Src kinases, Focal adhesion kinase, phospholipase C gamma, PI3 kinase/Akt and Nek3 (Clevenger et al. 2003, Miller et al. 2007). The protein tyrosine phosphatase SHP2 is recruited to the C terminal tyrosine of PRLR and may have a regulatory role (Ali & Ali 2000). PRLR phosphotyrosines can recruit insulin receptor substrates (IRS) and other adaptor proteins to the receptor complex (Bole-Feysot et al. 1998).
Female homozygous PRLR knockout mice are completely infertile and show a lack of mammary development (Ormandy et al. 1997). Hemizogotes are unable to lactate following their first pregnancy and depending on the genetic background, this phenotype can persist through subsequent pregnancies (Kelly et al. 2001).
所含基因
13 个基因