PRLR associates with JAK2

PRLR has no intrinsic kinase activity but associates with Janus kinase 2 (JAK2) (Lebrun et al. 1994, 1995, Campbell et al. 1994, Rui et al. 1994). PRLR to JAK2 binding has been described as constitutive but a recent computational model suggests that roughly half of dimerized Growth Hormone receptors are bound with JAK2 (Barua et al. 2009), a model that may apply to other receptors that promote JAK2 trans-activation. The box 1 region of PRLR is a membrane proximal proline-rich region in the intracellular domain, conserved in all members of the growth hormone rereptor family. This region is critical for JAK2 association; deletion of box 1 virtually abolishes PRLR signaling (Edery et al. 1994). Alanine substitutions of individual residues within box 1 of rat PRLR have shown that the most C-terminal proline (P269 in the Uniprot canonical sequence, 250 in the mature peptide) is critical for association with and subsequent activation of JAK2 (Pezet et al. 1997). It is not known whether the interaction of JAK2 with PRLR is direct or involves an adaptor protein.<br><br>When the receptor is activated by ligand binding JAK2 (receptor pre-bound or recruited after ligand binding) becomes activated and phosphorylates the dimerized receptor preferentially at Y611 (position 587 in the mature peptide), a consensus tyrosine phosphorylation site. This is followed by the phosphorylation, dimerization and nuclear translocation of STAT5. There are nine other tyrosines in the cytoplasmic domain, some of which may undergo phosphorylation and may participate in signal transduction.

PRLR（催乳素受体）不具备固有的激酶活性，但与Janus激酶2（JAK2）相联（Lebrun 等人，1994年，1995年，Campbell 等人，1994年，Rui 等人，1994年）。PRLR与JAK2的结合被视为组成性，但最近的一个计算模型表明，大约一半的二聚化生长激素受体与JAK2结合（Barua 等人，2009年），这一模型可能适用于其他促进JAK2跨激活的受体。PRLR的盒1区域是位于细胞内域的膜邻近脯氨酸富集区域，在生长激素受体家族的所有成员中均得以保守。这一区域对于JAK2的结合至关重要；盒1的缺失几乎消除了PRLR的信号传导（Edery 等人，1994年）。在大鼠PRLR的盒1区域内，单个氨基酸的丙氨酸替换表明最C端脯氨酸（Uniprot标准序列中的P269，成熟肽中的250）对于与JAK2的结合及其随后的激活至关重要（Pezet 等人，1997年）。目前尚不清楚JAK2与PRLR的相互作用是直接还是涉及适配蛋白。<br><br>当受体通过配体结合被激活时，JAK2（预先与受体结合或配体结合后募集）被激活，并优先在二聚化受体的Y611位（成熟肽中的位置587）进行磷酸化，这是一个共识酪氨酸磷酸化位点。随后，STAT5发生磷酸化、二聚化以及向细胞核的转位。细胞质域内还有九个其他酪氨酸，其中一些可能发生磷酸化，并可能参与信号传导。