SLAIN2

SLAIN2 is a microtubule plus-end tracking protein (+TIP) that promotes processive microtubule polymerization by serving as a molecular hub linking end-binding proteins to the microtubule polymerase ch-TOG (PMID:21646404). Its C-terminal domain binds EBs, CLIPs, and CLASPs, while its N-terminal domain engages ch-TOG, so that SLAIN2 enhances ch-TOG accumulation at growing plus ends and suppresses microtubule catastrophes (PMID:21646404, PMID:29044157); loss of the SLAIN2–ch-TOG complex disorganizes the interphase radial microtubule array (PMID:21646404). This catastrophe-suppressing activity is cell-cycle regulated: during mitosis SLAIN2 is hyperphosphorylated and its interactions with EBs and ch-TOG are disrupted, downregulating processive growth (PMID:21646404). The same activity is co-opted in specific physiological contexts — SLAIN2 is required for persistent plus-end growth supporting axon extension in developing neurons (PMID:23077057) and, by conferring microtubule resistance to compression, for pseudopod elongation during 3D mesenchymal cell invasion in vitro and in a mouse cancer model, independently of Rho GTPase activity, trafficking, or focal adhesions (PMID:27939686). SLAIN2 additionally localizes to pericentriolar material at the proximal end of centrioles (PMID:32256142).

1. 2006 Low

   Before any functional role was known, SLAIN2 was first identified as one of a novel, structurally distinct vertebrate-conserved gene family, establishing it as a defined protein worth characterizing.

   Evidence Comparative transcriptional profiling of mouse/human ES cells and bioinformatic sequence analysis

   PMID:16546155

   Open questions at the time

   • No direct experiment on SLAIN2 protein function
   • Domain architecture defined only computationally
   • No subcellular localization or interaction data
2. 2011 High

   Resolved what SLAIN2 does molecularly: it acts as a +TIP adaptor that bridges EB/CLIP/CLASP plus-end machinery to the polymerase ch-TOG to drive processive microtubule growth, answering how a polymerase is loaded onto growing ends.

   Evidence Reciprocal Co-IP, pulldown, domain mapping, and live-cell microtubule dynamics with RNAi in interphase cells

   PMID:21646404

   Open questions at the time

   • Stoichiometry and structural basis of the multi-partner complex not resolved
   • Whether EB and ch-TOG binding are simultaneous or competitive not defined
3. 2011 Medium

   Addressed how SLAIN2 activity is temporally controlled, showing mitotic hyperphosphorylation disrupts its EB and ch-TOG interactions to switch off processive polymerization during cell division.

   Evidence Phosphorylation analysis and Co-IP across cell-cycle stages with western blot

   PMID:21646404

   Open questions at the time

   • Responsible kinase not identified
   • Specific phosphosites not mapped
   • Functional consequence for spindle assembly not tested
4. 2011 High

   Established the cellular consequence of SLAIN2 loss — disorganization of the radial microtubule array — linking molecular catastrophe suppression to cytoskeletal architecture.

   Evidence RNAi knockdown and dominant-negative overexpression with immunofluorescence imaging of microtubule organization

   PMID:21646404

   Open questions at the time

   • Downstream effects on organelle positioning or polarity not examined
5. 2012 High

   Extended the +TIP role to a physiological context, showing SLAIN-mediated catastrophe suppression sustains plus-end growth required for axon extension in neurons.

   Evidence RNAi and dominant-negative in primary rat hippocampal neurons with live microtubule imaging and axon length measurement

   PMID:23077057

   Open questions at the time

   • In vivo neuronal requirement not tested
   • Relative contributions of SLAIN1 vs SLAIN2 not separated
6. 2016 High

   Demonstrated a disease-relevant function by isolating catastrophe suppression as the operative mechanism conferring microtubule mechanical resistance needed for 3D mesenchymal invasion, while excluding alternative pathways.

   Evidence RNAi, 3D invasion assays, mouse cancer model, plus exclusion of Rho GTPase, trafficking, and focal adhesion contributions

   PMID:27939686

   Open questions at the time

   • Whether SLAIN2 is required in human tumors not established
   • No genetic/causative human cancer mutation shown
7. 2017 Medium

   Provided structural-level definition of the SLAIN2 interaction interfaces with CLASP2 and ch-TOG, enabling design of minimal binding fragments.

   Evidence Cross-linking mass spectrometry with deletion analysis and biochemical binding assays

   PMID:29044157

   Open questions at the time

   • No high-resolution atomic structure
   • Single-lab in vitro mapping
8. 2017 Medium

   Revealed a non-cytoskeletal layer of SLAIN2 regulation — translational control of its mRNA by RARα in anucleate platelets, modulated by retinoic acid.

   Evidence RIP-seq, targeted RIP, UTR binding site analysis, and western blot in human platelets

   PMID:28981191

   Open questions at the time

   • Functional role of SLAIN2 in platelets not defined
   • Direct demonstration of translational repression not shown
9. 2020 Medium

   Identified a second localization for SLAIN2 at pericentriolar material and mapped a proximity interactome enriched for centriole and ciliogenesis proteins, broadening its potential cellular roles beyond plus ends.

   Evidence High-resolution imaging and BioID proximity labeling with mass spectrometry

   PMID:32256142

   Open questions at the time

   • Functional consequence of centrosomal localization not validated
   • BioID proximity does not confirm direct binding

• The identity of the mitotic kinase regulating SLAIN2, the functional significance of its centrosomal localization, and its role in platelets remain unresolved.
• Mitotic kinase and phosphosites unidentified
• Centriolar function untested
• Platelet/RARα axis function unknown