The ErbB4 receptor isoforms JM-a and JM-b differ within their extracellular juxtamembrane (eJM) domains. Here, ErbB4 isoforms are used as a model to address the effect of structural variation in the eJM domain of receptor tyrosine kinases (RTK) on downstream signaling. A specific JM-a-like sequence motif is discovered, and its presence or absence (in JM-b-like RTKs) in the eJM domains of several RTKs is demonstrated to dictate selective STAT activation. STAT5a activation by RTKs including the JM-a like motif is shown to involve interaction with oligosaccharides of N-glycosylated cell surface proteins such as β1 integrin, whereas STAT5b activation by JM-b is dependent on TYK2. ErbB4 JM-a- and JM-b-like RTKs are shown to associate with specific signaling complexes at different cell surface compartments using analyses of RTK interactomes and super-resolution imaging. These findings provide evidence for a conserved mechanism linking a ubiquitous extracellular motif in RTKs with selective intracellular STAT signaling.

ErbB4 受体亚型 JM-a 和 JM-b 在其细胞外近膜 (eJM) 结构域内有所不同。在这里，ErbB4 异构体用作模型来解决受体酪氨酸激酶 (RTK) 的 eJM 域中结构变异对下游信号的影响。发现了一个特定的 JM-a-like 序列基序，它在几个 RTK 的 eJM 域中的存在或不存在（在 JM-b-like RTK 中）被证明决定了选择性 STAT 激活。包括 JM-a 样基序的 RTK 对 STAT5a 的激活显示涉及与 N-糖基化细胞表面蛋白（例如 β1 整合素）的寡糖的相互作用，而 JM-b 对 STAT5b 的激活依赖于 TYK2。使用 RTK 相互作用组和超分辨率成像分析，ErbB4 JM-a- 和 JM-b 样 RTK 显示与不同细胞表面区室的特定信号复合物相关联。这些发现为将 RTK 中普遍存在的胞外基序与选择性胞内 STAT 信号联系起来的保守机制提供了证据。