Regulation of Jak kinases by intracellular leptin receptor sequences.
Leptin signals the status of body energy stores via the leptin receptor (LR), a member of the Type I cytokine receptor family. Type I cytokine receptors mediate intracellular signaling via the activation of associated Jak family tyrosine kinases. Although their COOH-terminal sequences vary, alternatively spliced LR isoforms (LRa-LRd) share common NH(2)-terminal sequences, including the first 29 intracellular amino acids. The so-called long form LR (LRb) activates Jak-dependent signaling and is required for the physiologic actions of leptin. In this study, we have analyzed Jak activation by intracellular LR sequences under the control of the extracellular erythropoeitin (Epo) (Epo receptor/LRb chimeras). We show that Jak2 is the requisite Jak kinase for signaling by the LRb intracellular domain and confirm the requirement for the Box 1 motif for Jak2 activation. A minimal LRb intracellular domain for Jak2 activation includes intracellular amino acids 31-48. Although the sequence requirements for intracellular amino acids 37-48 are flexible, intracellular amino acids 31-36 of LRb play a critical role in Jak2 activation and contain a loose homology motif found in other Jak2-activating cytokine receptors. The failure of short form sequences to function in Jak2 activation reflects the absence of this motif.
Section on Obesity, Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Carolyn
C
Kloek
Asma K
AK
Haq
Sarah L
SL
Dunn
Hugh J
HJ
Lavery
Alexander S
AS
Banks
Martin G
MG
Myers
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D053614:Janus Kinase 2; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology*; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C515447:leptin receptor, mouse; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2