. 2021 Mar 26;22(7):3439. doi: 10.3390/ijms22073439

Table 6.

Phenotypes observed in AnxA6 in vivo models.

(a) AnxA6 and Cardiac Function
Tissue/Disease	Model	Phenotype	Mechanism	Ref
Cardiomyopathy Heart failure	Heart-specific AnxA6 WT/mutant overexpression	Amplitude Ca²⁺ transients; Ca²⁺ flux and signaling; Contractility	Ca²⁺-dependent ion pumps/channels in cardiomyocytes	[306,308]
Cardiac function	AnxA6-KO cardiomyocytes	Ca²⁺ flux and signaling; Contractility	Ca²⁺-dependent ion pumps/channels	[307]
Cardiac function	AnxA6 KO-mice	Normal cardiac function	Redundancy?	[312]
(b) AnxA6 and Skeletal Development
Tissue/Disease	Model	Phenotype	Mechanism	Ref
Bone and cartilage development	AnxA6 KO-mice; AnxA5/A6 Double-KO mice	Normal skeletal development	Redundancy?	[238,239]
Bone and cartilage development	AnxA6 KO-mice, Newborns	Reduced mineralization of growth plate cartilage; Delayed chondrocyte differentiation	Loss of AnxA6-dependent PKCα translocation and signaling	[316]
Osteoarthritis	AnxA6 KO-mice	Reduced knee cartilage destruction	Loss of AnxA6/p65 (NFκB) interaction	[317,318]
Pain in osteoarthritis	AnxA6 KO-mice	Increased sensitivity to mechanical/chronic pain stimuli	Increased cation channel Piezo2 activity in sensory neurons	[320]
(c) AnxA6 and Immune Response
Tissue/Disease	Model	Phenotype	Mechanism	Ref
Immune system	AnxA6 KO-mice	Normal B and T cell development	Redundancy?	[314]
Immune response	AnxA6 KO-mice	Reduced CD4⁺ T lymphocyte activation	Membrane organisation; IL-2 signaling	[321]
(d) AnxA6 and Homeostasis
Tissue/Disease	Model	Phenotype	Mechanism	Ref
Membrane order	AnxA6-KO MEFs	Microdomain organisation	Membrane domain/lipid distribution	[319]
Ca²⁺ homeostasis	AnxA6-KO (liver, retina) AnxA6-KO MEFs	Dysfunctional mitochondria	Loss of AnxA6/Drp1 interaction	[289]
(e) AnxA6 and Lipid/Glucose Homeostasis
Tissue/Disease	Model	Phenotype	Mechanism	Ref
Adipose tissue	AnxA6 KO-mice	Reduced WAT weight gain after HFD; Increased adiponectin secretion	Triglyceride metabolism; Lipid droplet functions; Adipokine secretion	[324,325,326]
Liver regeneration	AnxA6 KO-mice	Hypoglycemia; De-regulated hepatic gluconeogenesis	Loss of alanine uptake and SNAT4 transporter cell surface localization	[329]
HFD-induced fatty liver and insulin resistance	AnxA6 KO-mice	Altered insulin signaling; Increased glycogen storage; Failure to downregulate hepatic gluconeogenesis	Loss of AnxA6 scaffold and membrane transport functions	[326]
Neuronal damage, motor coordination	AnxA6 KO-mice; NPC1 KO-mice; AnxA6/NPC1 Double-KO mice	Normal in AnxA6-KO; Cerebellar degeneration similar in NPC1-KO and AnxA6/NPC1 Double-KO		[339]
Liver dysfunction	AnxA6 KO-mice; NPC1 KO-mice; AnxA6/NPC1 Double-KO mice	AnxA6/NPC1 Double-KO compared to NPC1-KO: Increased liver inflammation; Altered mitochondrial morphology; Higher turnover of neutral lipids and glycogen; Reduced lifespan	Loss of AnxA6 scaffold to control cholesterol homeostasis, inter-organelle communication and macrophage infiltration	[340]
(f) AnxA6 and Cancer
Disease	Model	Phenotype	Mechanism	Ref
EGFR-related cancer	AnxA6 overexpression in A431 xenografts	Reduced tumour growth; Impact on EGFR-targeted drug efficacy	AnxA6-mediated and PKCα- and p120GAP- dependent inhibition of EGFR/Ras/MAPK signaling	[345,346]
Triple-negative breast cancer (TNBC)	AnxA6 depletion in BT-549 xenografts	Early onset and rapid tumour growth; Impact on EGFR-targeted drug efficacy	AnxA6- and RASGRF2- dependent EGFR/Ras/MAPK signaling	[347,348,349]
Drug resistance in breast cancer	MMTV-PyMT and 4T1 breast cancer models	Chemotherapy-elicited secretion of AnxA6-containing EVs from tumours with enhanced metastatic capacity	Pulmonary NFκB-dependent endothelial activation, elevated cytokine secretion	[351]
Pancreatic ductal adenocarcinoma (PDAC)	PDAC mouse model	ANXA6-depleted EVs from CAFs impaired PDAC and metastasis	CAF-cancer cell communication via ANXA6/LRP1/TSP1	[352]
Gastric cancer	NUGC3 xenografts	AnxA6-containing EVs from CAFs contribute to drug resistance	AnxA6-mediated activation of integrin β1, FAK and YAP1	[353]
(g) AnxA6 and Membrane Repair
Disease	Model	Phenotype	Mechanism	Ref
Muscle dystrophy	AnxA6-KO in zebrafish	Impaired membrane repair	Cooperation with dysferlin	[293]
Muscle dystrophy	Mouse models with Dysferlin mutations	Impaired AnxA6 recruitment for membrane repair	Cooperation with dysferlin and other annexins to seal injured membrane	[354,355,356]
Muscle dystrophy	Mouse models for muscular dystrophy	AnxA6 is a modifier gene required for membrane repair after muscle injury	AnxA6 mutants contribute to defects in sarcolemma resealing	[295]
Muscle dystrophy	Mouse models for muscular dystrophy	Delivery of AnxA6 promotes membrane repair in muscle	AnxA6 upregulation or administration of recombinant AnxA6 improves repair	[357,358]
Muscle dystrophy	Myofibers from ANO5 KO-mice	Loss of Anx-dependent cap formation at injury site	Lack of AnxA6 accumulation at injury site	[287]

Abbreviations: ANO5, anoctamin-5; Anx, annexin; Ca²⁺, calcium; CAFs, cancer associated fibroblasts; Drp1, dynamin-related protein 1; EGFR, epidermal growth factor receptor; EVs, extracellular vesicles; FAK, focal adhesion kinase; HFD, high-fat diet; IL, interleukin; KO, knockout; LRP1, low density lipoprotein receptor related protein 1; MAPK, mitogen-activated protein kinase; MMTV-PyMT, mouse mammary tumor virus-polyoma middle tumor-antigen; NFκB, nuclear factor kappa B; p120GAP, p120 GTPase activating protein; PDAC, pancreatic ductal adenocarcinoma; PKCα, protein kinase Cα; RASGRF2, Ras protein specific guanine nucleotide exchange factor; SNAT4, sodium-coupled neutral amino acid transporter 4; TNBC, triple negative breast cancer; TSP1, thrombospondin 1; WAT, white adipose tissue. YAP1, yes-associated protein 1.