Table 2 Partners interacting with SCUBE members in biological and pathological processes

SCUBE1

SCUBE1

EGF-like

Platelet agglutination

Formation of homo-oligomeric complexes

[2, 20]

SCUBE2

Formation of hetero-oligomeric complexes

[2]

SCUBE3

Formation of hetero-oligomeric complexes

[5, 21]

BMP2

Brain formation and zebrafish primitive hematopoiesis

When co-expressed in “signal-producing” cells, the C-terminal CR and CUB domains of SCUBE1 interact with BMP2 to function as a BMP antagonist. When expressed in “signal-receiving” cells, zebrafish Scube1 forms a complex with Bmp ligands and its receptors, behaving as a BMP coreceptor to augment BMP signaling activity

[8, 20]

PEAR1

EGF-like and CUB

SCUBE1 binds PEAR1 through EGF-like repeats and CUB domain, possibly for platelet agglutination

[72]

Caveolin-1

Spacer and CUB

SCUBE1 forms a complex with caveolin-1 via Spacer and CUB domains for its recruitment into lipid raft microdomains

[26]

VEGFR2

Zebrafish angiogenesis

SCUBE1 cannot interact with VEGF, which suggests that SCUBE1 may not function as a coreceptor for VEGF

[23]

BMP7

Protects against AKI

SCUBE1 acts as a BMP coreceptor by binding to BMP7 and its receptors and facilitating BMP7 signaling

[49]

BMPRIB

BMPRII

FLT3 ligand

Spacer and CUB

Promotes AML

SCUBE1 might form a complex with FLT3 ligand and FLT3 via Spacer and CUB domains to facilitate pathological FLT3-LYN signaling

[44]

FLT3

Spacer and CUB

SCUBE2

SCUBE1

Formation of hetero-oligomeric complexes

[2]

SCUBE2

Formation of homo-oligomeric complexes

[2]

SCUBE3

Formation of hetero-oligomeric complexes

[21]

BMP2

CR and CUB

Acts as breast tumor suppressor

The C-terminal region of SCUBE2 binds BMP protein and acts as a BMP antagonist

[112]

SHH

CUB

Endochondral bone formation

SCUBE2 can specifically interact with SHH, IHH, and PTCH1 and enhance the HH signaling activity within the cholesterol-rich raft microdomains of the plasma membrane (HH signaling enhancer)

[4, 45]

IHH

CUB

PTCH1

Spacer and CUB

Caveolin-1

CUB

E-cadherin

EGF-like

Acts as breast tumor suppressor

1. SCUBE2 co-localizes with E-cadherin at MCF-7 cell contacts, acting as a tumor suppressor for breast cancer

2. SCUBE2 forms a complex with E-cadherin mainly through its EGF-like repeats and inhibits breast-cancer cell migration and invasion via the reversal of EMT

[22, 51]

VEGF

EGF-like

Promotes tumor angiogenesis

1. SCUBE2 colocalizes and interacts with VEGFR2 in HUVECs

2. SCUBE2 directly binds to VEGF-A₁₆₅ and VEGFR2

[23]

VEGFR2

CUB

SCUBE3

SCUBE1

Formation of hetero-oligomeric complexes

[5, 21]

SCUBE2

Formation of hetero-oligomeric complexes

[21]

SCUBE3

Formation of homo-oligomeric complexes

[5, 21]

TGF-β1

Promotes cardiac hypertrophy

SCUBE3 forms a complex with TGF-β1

[170]

TβR-II

CUB

Promotes lung cancer progression

SCUBE3 binds to TβR-II via its C-terminal CUB domain, promoting lung cancer via EMT

[48]

FGF8

EGF-like, Spacer, and CUB

Zebrafish fast muscle development

SCUBE3 interacts with FGF8/FGFR4 to enhance FGF8 signaling

[9]

FGFR4

Spacer and CUB

BMP2

CUB

Craniofacial and skeletal development

SCUBE3 binds to BMP and BMP receptors, acting as an enhancer for BMP signaling; involved in BMP-dependent osteoblast differentiation

[21]

BMP4

BMP7

BMPRIA

BMPRIB

BMPRII

VEGFR2

SCUBE3 cannot interact with VEGF, which suggests that SCUBE3 may not function as a coreceptor for VEGF

[23]