Direct Association of Sprouty-related Protein with an EVH1 Domain (SPRED) 1 or SPRED2 with DYRK1A Modifies Substrate/Kinase Interactions

• Published in: The Journal of biological chemistry Vol. 285; no. 46; pp. 35374 - 35385
• Main Authors: Li, Dan, Jackson, Rebecca A., Yusoff, Permeen, Guy, Graeme R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.11.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation; Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Binding Sites - genetics; Binding, Competitive; Cell Line, Tumor; Cell Proliferation; Cysteine - genetics; Cysteine - metabolism; Dual Specificity Kinase; Dyrk Kinases; DYRK1A; FGFR; HEK293 Cells; Humans; Immunoblotting; Immunoprecipitation; Mice; Molecular Sequence Data; p53; Protein Binding; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Receptor Tyrosine Kinase; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA Interference; Signal Transduction; SPRED; Sprouty; STAT Transcription Factor; STAT3; STAT3 Transcription Factor - metabolism; Substrate Specificity; Tau; tau Proteins - metabolism; Tumor Suppressor Protein p53 - metabolism; Two-Hybrid System Techniques; STAT Transcription Factor; SPRED; Dual Specificity Kinase; STAT3; DYRK1A; Tau; FGFR; Sprouty; p53; Receptor Tyrosine Kinase
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M110.148445

The mammalian SPRED (Sprouty-related protein with an EVH1 domain) proteins include a family of three members, SPRED1–3. Currently, little is known about their biochemistry. The best described, SPRED1, has been shown to inhibit the Ras/ERK pathway downstream of Ras. All three SPREDs have a cysteine-rich domain (CRD) that has high homology to the CRD of the Sprouty family of proteins, several of which are also Ras/ERK inhibitors. In the belief that binding partners would clarify SPRED function, we assayed for their associated proteins. Here, we describe the direct and endogenous interaction of SPRED1 and SPRED2 with the novel kinase, DYRK1A. DYRK1A has become the subject of recent research focus as it plays a central role in Caenorhabditis elegans oocyte maturation and egg activation, and there is strong evidence that it could be involved in Down syndrome in humans. Both SPRED1 and SPRED2 inhibit the ability of DYRK1A to phosphorylate its substrates, Tau and STAT3. This inhibition occurs via an interaction of the CRD of the SPREDs with the kinase domain of DYRK1A. DYRK1A substrates must bind to the kinase to enable phosphorylation, and SPRED proteins compete for the same binding site to modify this process. Our accumulated evidence indicates that the SPRED proteins are likely physiological modifiers of DYRK1A.