The cyclin-dependent kinase activator, Spy1A, is targeted for degradation by the ubiquitin ligase NEDD4.
Spy1A is a cyclin-like protein required for progression through the G(1)/S phase of the cell cycle. Elevated Spy1A protein levels have been implicated in tumorigenesis and are attributed to overriding the DNA damage response and enhancing cell proliferation. Understanding how Spy1A is produced and degraded is essential in resolving how it contributes to normal and abnormal growth processes. Herein, we demonstrate that Spy1A is degraded in a cell cycle-dependent manner during mitosis via the ubiquitin-proteasome system. We have resolved the E3 ligase and essential phosphorylation sites mediating Spy1A degradation. Furthermore, we have determined that non-degradable forms of Spy1A do not trigger cell cycle arrest but, rather, contribute to uncontrolled cell growth. Further investigation into the regulation of Spy1A may reveal novel strategies for understanding the etiology and progression of specific growth disorders.
Al Sorkhy
Mohammad
M
University of Windsor, Windsor, Ontario N9B 3P4.
Craig
Ryan
R
University of Windsor, Windsor, Ontario N9B 3P4.
Market
Brenna
B
University of Western Ontario, London, Ontario N6A 5C1, Canada.
Ard
Ryan
R
University of Windsor, Windsor, Ontario N9B 3P4.
Porter
Lisa A
LA
University of Windsor, Windsor, Ontario N9B 3P4. Electronic address: lporter@uwindsor.ca.
D001483:Base Sequence; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D056827:Endosomal Sorting Complexes Required for Transport; D006801:Humans; D006868:Hydrolysis; D016297:Mutagenesis, Site-Directed; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D017931:DNA Primers; D056827:Endosomal Sorting Complexes Required for Transport; C486530:SPDYA protein, human; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; D044767:Ubiquitin-Protein Ligases