PLEKHA5

PLEKHA5 is a multi-domain scaffold protein that couples phosphoinositide-defined membrane microdomains to protein trafficking and to cell proliferation and metastasis programs. Through its PH domain it binds the phosphoinositides PI3P, PI4P, PI5P, and PI(3,5)P2, and this PH domain directs its localization along the lateral plasma membrane (PMID:22037487, PMID:34568338). Via tandem WW domains PLEKHA5 binds the adaptor PDZD11, and this interaction both mediates their joint association with cytoplasmic microtubules and recruits PDZD11 to plasma membrane sites (PMID:34568338, PMID:34613798). Functionally, the WW-PLEKHA–PDZD11 complex promotes PDZD11 binding to the C-terminus of the Menkes copper ATPase ATP7A and is required for efficient anterograde targeting of ATP7A to the cell periphery, so that loss of the complex impairs copper extrusion and elevates intracellular copper (PMID:34613798). In cancer contexts, PLEKHA5 is tyrosine-phosphorylated downstream of the Met receptor in Met-amplified gastric carcinoma cells, where it supports survival and glycolytic metabolism and restrains JNK-driven apoptosis (PMID:33677467), and it drives the G1-to-S transition in melanoma by destabilizing the tumor suppressor PDCD4 and engaging PI3K/AKT/mTOR signaling (PMID:31769872). PLEKHA5 is required for melanoma brain-metastatic cell viability, invasion, and blood-brain-barrier transmigration (PMID:25316811), yet acts as a metastasis suppressor in BRCA1-associated breast cancer (PMID:32978388), indicating context-dependent roles in tumor dissemination.

1. 2011 Medium

   Established the biochemical basis for PLEKHA5 membrane association by showing its PH domain reads specific phosphoinositides, defining it as a candidate phosphoinositide-binding scaffold.

   Evidence Protein-lipid overlay assays and subcellular fractionation of two splice variants in vitro

   PMID:22037487

   Open questions at the time

   • Lipid binding shown by a single overlay method without cellular validation
   • No functional consequence of phosphoinositide binding established at this stage
   • Functional difference between L- and S-isoforms unresolved
2. 2014 Medium

   Provided the first functional role for PLEKHA5, showing it is selectively required for brain-tropic melanoma cell survival, invasion, and BBB transmigration rather than for parental tumor cell viability.

   Evidence siRNA knockdown with in vitro BBB transmigration, invasion, and viability assays in brain-tropic vs parental melanoma lines

   PMID:25316811

   Open questions at the time

   • Molecular mechanism linking PLEKHA5 to transmigration not defined
   • No in vivo brain metastasis confirmation
   • Effector pathways downstream of PLEKHA5 not identified
3. 2019 Medium

   Connected PLEKHA5 to cell cycle control, showing it promotes the G1-to-S transition by destabilizing PDCD4 and engaging PI3K/AKT/mTOR signaling.

   Evidence Stable knockdown and overexpression with cell cycle analysis, PDCD4/PI3K-AKT-mTOR Western blotting, and xenograft models

   PMID:31769872

   Open questions at the time

   • Mechanism by which PLEKHA5 controls PDCD4 protein stability undefined
   • Whether PI3K/AKT/mTOR changes are direct or secondary unresolved
   • No direct enzymatic activity assigned to PLEKHA5
4. 2020 Medium

   Revealed context-dependence of PLEKHA5 in metastasis by identifying it as a metastasis suppressor in BRCA1-associated breast cancer, opposite to its pro-metastatic role in melanoma.

   Evidence Single-cell whole-exome sequencing combined with in vivo loss-of-function metastasis assays in mouse/human BRCA1-associated breast cancer

   PMID:32978388

   Open questions at the time

   • Mechanism of metastasis suppression not defined
   • Reconciliation with pro-metastatic melanoma role unexplained
   • Tissue-specific determinants of opposing roles unknown
5. 2021 High

   Defined the core molecular machine: WW-domain binding to PDZD11 builds a complex that, together with PH-domain phosphoinositide reading, recruits the adaptor to membranes and microtubules and directs ATP7A trafficking for copper extrusion.

   Evidence CRISPR knockout, reciprocal pull-downs, immunofluorescence with domain mutants/chimeras, and copper/metallothionein measurements

   PMID:34568338 PMID:34613798

   Open questions at the time

   • Structural basis of WW–PDZD11 and PDZD11–ATP7A interactions not resolved
   • How phosphoinositide binding is regulated in cells unknown
   • Link between trafficking scaffold function and cancer phenotypes unestablished
6. 2021 Medium

   Placed PLEKHA5 downstream of an oncogenic receptor tyrosine kinase, showing it is Met-phosphorylated and required for survival and metabolic homeostasis of Met-amplified gastric carcinoma cells.

   Evidence Phosphoproteomics, siRNA knockdown, apoptosis and glycolysis assays, JNK analysis, and in vivo peritoneal dissemination model

   PMID:33677467

   Open questions at the time

   • Functional consequence of specific tyrosine phosphorylation sites not dissected
   • Mechanism linking PLEKHA5 to glycolysis and JNK suppression undefined
   • Whether scaffold/trafficking function underlies the survival role unknown
7. 2025 Low

   Extended PLEKHA5 function to lipid storage and a TNFα-responsive transcriptional axis in melanoma.

   Evidence RNA interference with transcriptomics, proteomics, and lipid metabolomics in vitro and in vivo

   PMID:40462127

   Open questions at the time

   • No direct mechanism for how PLEKHA5 controls neutral lipid metabolism
   • FCRLA downstream relationship inferred from expression data only
   • Not independently confirmed
8. 2025 Low

   Attributed isoform-specific oncogenic activity to PLEKHA5-L in melanoma proliferation and migration.

   Evidence RNAi, lentiviral overexpression, proliferation/migration assays, and RNA sequencing

   PMID:40356756

   Open questions at the time

   • HRAS/AKT3 and other effectors inferred from transcriptomics without causal validation
   • Molecular basis of isoform-specific activity undefined
   • Single-lab transcriptomic pathway inference

• How PLEKHA5's defined scaffold/trafficking biochemistry mechanistically produces its divergent, tissue-specific roles in proliferation, survival, and metastasis remains unresolved.
• No structural model of the WW-PLEKHA–PDZD11–ATP7A complex
• Mechanism reconciling pro-metastatic vs metastasis-suppressor contexts unknown
• Direct link between phosphoinositide binding/trafficking function and cancer signaling not established