CALD1

CALD1 (caldesmon) is an actin-associated cytoskeletal protein whose isoforms govern smooth muscle contractility and cell motility, and which is repeatedly co-opted in cancer to control proliferation, EMT, and invasion (PMID:40104711, PMID:39476475). Its high-molecular-weight isoform marks the contractile smooth muscle phenotype and is upregulated by endothelin-1 acting through ETAR/ETBR receptors, with elevated CALD1 linked to stronger vascular contraction (PMID:39476475), while the low-molecular-weight isoform localizes to motility-related protrusions such as filopodia, lamellipodia, and podosomes consistent with a role in cell migration (PMID:19329885). In ovarian cancer CALD1 acts to restrain invasion: its loss reduces F-actin stress fibers, loosens cytoskeletal organization, and decreases Vinculin expression and focal adhesion number (PMID:40104711). In several other cancers CALD1 instead promotes malignant behavior through downstream signaling, activating the MAPK pathway (Ras, p-P38, p-ERK1/2) (PMID:38025524) and the PI3K-Akt-mTOR axis with concomitant PTEN loss to drive proliferation and EMT (PMID:38577446), and activating JAK/STAT signaling to upregulate PD-L1 (CD274) (PMID:34733993). CALD1 is post-translationally inactivated by ERK1/2-mediated phosphorylation recruited via AHSA1 (PMID:36230524), and its expression is controlled by METTL14-dependent m6A methylation (PMID:37017680) and by negative regulation through miR-1278 (PMID:38025524) and miR-148a-5p (PMID:41171370); in H. pylori-positive gastric cancer, de-repressed CALD1 in cancer-associated fibroblasts drives collagen VI secretion that engages tumoral SDC4 to promote tumor growth (PMID:41171370).

1. 2007 Low

   Established where the low-molecular-weight caldesmon isoform acts in cells, linking it to the migratory machinery rather than only contraction.

   Evidence Immunohistochemistry of motility-related protrusions in tumor vasculature sections

   PMID:19329885

   Open questions at the time

   • Localization only — no functional motility assay or rescue
   • Does not establish causal role in migration
   • Isoform-specific function not dissected mechanistically
2. 2021 Medium

   Connected CALD1 to immune evasion by showing it drives PD-L1 expression through a defined kinase pathway.

   Evidence Overexpression/knockdown in bladder cancer cells with Ruxolitinib JAK inhibition, Western blot, flow cytometry

   PMID:34733993

   Open questions at the time

   • Mechanism linking CALD1 to JAK/STAT activation unresolved
   • Single cancer context
   • No direct biochemical interaction shown
3. 2022 Medium

   Defined how CALD1 activity is post-translationally controlled, placing it downstream of an AHSA1–ERK1/2 axis that phosphorylates and inactivates it.

   Evidence Gain/loss-of-function in vitro and in vivo, SCH772984 ERK inhibition, Western blot for phospho-CALD1, knockdown rescue

   PMID:36230524

   Open questions at the time

   • Phosphosites on CALD1 not mapped
   • Direct AHSA1–CALD1 vs indirect recruitment not distinguished
   • Functional consequence of inactivation on actin binding not measured
4. 2023 Medium

   Identified upstream transcriptional/epigenetic regulators of CALD1 (m6A and microRNA) and a downstream MAPK effector pathway.

   Evidence MeRIP/qRT-PCR with METTL14 silencing and rescue (OSCC); dual luciferase miR-1278 binding, CCK-8/Transwell, MAPK Western blots (gastric)

   PMID:37017680 PMID:38025524

   Open questions at the time

   • m6A reader mediating CALD1 mRNA fate not identified
   • How CALD1 protein activates MAPK is not mechanistically defined
   • Single-lab findings per cancer type
5. 2024 Medium

   Extended CALD1's pro-tumor signaling to the PI3K-Akt-mTOR axis driving EMT.

   Evidence siRNA/overexpression in AGS and MKN45 cells, pharmacological PI3K-Akt inhibition, Western blot, in vivo xenograft

   PMID:38577446

   Open questions at the time

   • Link between CALD1 and PI3K activation not biochemically defined
   • Relationship to the MAPK and JAK/STAT effects in other studies unclear
6. 2025 Medium

   Revealed a context-dependent tumor-suppressive role (ovarian) via cytoskeletal/focal adhesion maintenance, and a stromal CAF-driven pro-tumor axis (gastric).

   Evidence shRNA knockdown with invasion assay and F-actin/Vinculin immunofluorescence (ovarian); miR/transcriptome and single-cell sequencing, co-culture, CDX/PDX, miR-148a-5p agomir (gastric)

   PMID:40104711 PMID:41171370

   Open questions at the time

   • Molecular basis for opposing tumor-suppressor vs oncogenic roles unresolved
   • Direct CALD1 role in collagen VI secretion vs correlative not established
   • Cell-type specificity of CALD1 function not reconciled

• It remains unresolved how CALD1's core actin-binding/cytoskeletal function mechanistically dictates its opposing tumor-suppressive versus oncogenic outcomes across tissues, and how the multiple signaling pathways (MAPK, PI3K-Akt, JAK/STAT) are causally linked to its molecular activity.
• No structural or biochemical reconciliation of context-dependent roles
• Phosphoregulation site mapping absent
• Direct effector mechanism upstream of signaling pathways undefined