The ErbB4 receptor isoforms JM-a and JM-b differ within their extracellular juxtamembrane (eJM) domains. Here we used ErbB4 isoforms as a model to address whether structural variation in the eJM domain of receptor tyrosine kinases (RTK) affects downstream signaling. Analysis of ErbB4 interactome and super-resolution cell imaging indicated association of the JM-a- and JM-b-like receptors with specific signaling complexes at different cell surface compartments. A JM-a-specific sequence motif was discovered, and its presence in the eJM domains of several other human RTKs predicted selective STAT activation indicating a conserved RTK signaling mechanism. The RTKs with the JM-a-like eJM motif activated STAT5a, and those that were JM-b-like (lacking the JM-a-like motif) activated STAT5b and STAT3. TYK2 was found to be necessary for JM-b-stimulated STAT5b activation. The activation of STAT5a by the JM-a-like receptors, in turn, involved specific interaction with oligosaccharides N-linked to cell surface glycoproteins such as β1 integrin. These findings provide evidence for a mechanism linking a ubiquitous extracellular motif in RTKs with selective intracellular STAT signaling.