WDCP

WDCP (C2orf44/MMAP) is a WD-repeat and coiled-coil oligomeric protein that functions as a mitotic scaffold coordinating the MRN complex with spindle dynamics (PMID:25469238, PMID:30297404). During mitosis it directly binds MRE11 and is required for optimal stability of the MRE11-RAD50-NBS1 complex, assembling a mitosis-specific complex (mMRN) that localizes to spindles; both WDCP and MRE11 are hyperphosphorylated by PLK1, and this modification is required for mMRN assembly, which in turn enables PLK1 to engage and activate the microtubule depolymerase KIF2A to drive spindle turnover and faithful chromosome segregation (PMID:30297404). WDCP also carries a C-terminal proline-rich segment that binds the SH3 domain of the Src-family kinase Hck and is tyrosine-phosphorylated upon Hck co-expression (PMID:25469238). Its self-association into oligomers underlies its oncogenic role: in colorectal cancer WDCP is recurrently fused to ALK, where the imposed oligomeric architecture drives constitutive ALK kinase activation as an oncogenic driver (PMID:25469238, PMID:22327622).

1. 2012 Medium

   Established WDCP as a clinically relevant oncogenic locus by identifying it as a recurrent ALK fusion partner in colorectal cancer, raising the question of how a poorly characterized ORF could drive kinase activation.

   Evidence Next-generation sequencing of colorectal tumor specimens

   PMID:22327622

   Open questions at the time

   • Oncogenic mechanism inferred from fusion architecture but not reconstituted in vitro
   • Native function of WDCP not addressed
   • Frequency and clinical impact across cohorts not defined here
2. 2014 Medium

   Began defining WDCP's biochemical properties by showing it binds the Hck SH3 domain via a proline-rich segment and is tyrosine-phosphorylated by Hck, placing it in a Src-family kinase interaction context.

   Evidence Cloning, co-expression, SH3 pulldown and tyrosine phosphorylation assays in a single lab

   PMID:25469238

   Open questions at the time

   • No structural validation of the SH3 interaction
   • Functional consequence of Hck phosphorylation unknown
   • Not independently replicated
3. 2014 Low

   Demonstrated that WDCP self-associates into oligomers, providing the structural basis later invoked to explain constitutive ALK activation in the fusion.

   Evidence Chromatographic fractionation of cell lysates

   PMID:25469238

   Open questions at the time

   • Single biochemical method without structural validation
   • Oligomerization domain and stoichiometry not defined
   • Link to ALK fusion activation not directly tested
4. 2018 High

   Defined WDCP's endogenous function as a mitotic scaffold that stabilizes the MRN complex (mMRN) and couples PLK1 phosphorylation to KIF2A-dependent spindle dynamics and chromosome segregation.

   Evidence Reciprocal Co-IP, colocalization imaging, siRNA knockdown with spindle/segregation phenotypes, phosphorylation assays, and PLK1-KIF2A epistasis in a single study

   PMID:30297404

   Open questions at the time

   • PLK1 phosphosites on WDCP not mapped
   • Structural basis of MRE11 binding not resolved
   • Relationship between mitotic scaffold function and ALK-fusion oncogenesis not connected

• How WDCP's oligomerization, Hck/SH3 binding, and mitotic mMRN scaffolding functions integrate—and whether any relate mechanistically to its oncogenic ALK-fusion role—remains unresolved.
• No structural model of WDCP or its domains
• Physiological role of Hck-mediated tyrosine phosphorylation unknown
• Whether normal WDCP function is co-opted in the ALK fusion is untested