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The RYK Receptor Family

  • Chapter
Receptor Tyrosine Kinases: Family and Subfamilies

Abstract

Members of the related to tyrosine kinase (RYK) receptor subfamily display a small extracellular region featuring a Wnt inhibitory factor domain, a single transmembrane helix with a strong propensity to self-associate, and an intracellular region exhibiting several abnormal protein sequence motifs that contribute to a protein tyrosine kinase domain. These sequence deviations are characteristic and strongly associated with a lack of detectable intrinsic protein kinase activity, implying that RYK receptors form a subfamily of pseudokinases within the receptor-type protein tyrosine kinase group. RYK subfamily members are receptors for the Wnt family of acylated glycoproteins during embryonic development and in postnatal axon pathfinding. Emerging details of Wnt/RYK-triggered β-catenin-dependent and β-catenin-independent signaling cascades regulate metazoan cell polarity and fate patterning, survival, proliferation, drug resistance, axon pathfinding and topographic mapping, migration, and the selection of appropriate target sites by cell processes. Sequential Notch-like proteolytic events that target distinct sites in RYK contribute in significant but mechanistically ill-defined ways to signaling via the coupled release of an extracellular fragment with predicted Wnt-binding activity and generation of a cytoplasmic/nuclear fragment that regulates cell fate in the mammalian central nervous system. These exciting discoveries, together with early insights into the involvement of RYK in mammalian pathology, indicate that RYK, the products of its proteolysis, and its protein partners represent attractive candidates for therapeutic targeting in a wide variety of animal and human conditions.

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Abbreviations

AC:

Anterior commissure

AF-6:

MLLT4 myeloid/lymphoid or mixed-lineage leukemia (trithorax homolog, Drosophila) translocated to 4 (Homo sapiens (human)), ALL-1 fused gene from chromosome 6

AL:

Drosophila antennal lobe

ALM:

Anterior lateral microtubule

AP:

Anterior–posterior axis

APP:

Amyloid precursor protein

ATP:

Adenosine 5′-triphosphate

ATP5O:

ATP synthase, H+ transporting, mitochondrial F1 complex, O subunit

βarr:

β-Arrestin

βgeo:

β-Galactosidase-neomycin phosphotransferase II fusion protein

CAM-1:

CAN cell migration defective-1

CaMKII:

Ca2+/calmodulin-dependent protein kinase II α

CASK:

Calcium/calmodulin-dependent serine protein kinase (MAGUK family)

CCK4:

Colon carcinoma kinase 4

Cdc37:

Cell division cycle 37

cDNA:

Complementary DNA

CE:

Convergent extension

CELSR2:

Cadherin EGF LAG seven-pass G-type receptor 2

CFZ-2:

Caenorhabditis frizzled homolog 2

CNS:

Central nervous system

CK1α:

Casein kinase 1α

COSMIC:

Catalogue of Somatic Mutations in Cancer

CST:

Corticospinal tract

CWN-1:

C. elegans WNT family-1

CWN-2:

C. elegans WNT family-2

Da:

Dalton

DA:

Dopaminergic

DL:

Dorsolateral

DLC:

Dorsolateral cluster

DNA-PKcs:

Catalytic subunit of the DNA-dependent protein kinase

DRG:

Dorsal root ganglion

dnt :

doughnut on 2

drl :

derailed

Drl-2 :

derailed-2

DRS:

Dominant Robinow syndrome

DSG2:

Desmoglein 2

DsRed2:

Discosoma sp. red fluorescent protein variant 2

DV:

Dorsal–ventral axis

Dvl:

Dishevelled

E:

Rodent embryonic day

ECM:

Extracellular matrix

EGL-20:

Egg-laying defective-20

ERBB3:

v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3

ERBB4:

v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4

Eph:

Erythropoietin-producing hepatoma

FISH:

Fluorescence in situ hybridization

Fzd:

Frizzled

GABA:

γ-Aminobutyric acid

GFP:

Green fluorescent protein

GPR125:

G protein-coupled receptor 125

GSK3:

Glycogen synthase kinase 3

hpf:

Hours postfertilization

Hsp90:

Heat shock protein 90 kDa

Htt:

Huntingtin

IP3R:

Inositol 1,4,5-trisphosphate receptor

JAK2:

Janus kinase 2

JH2:

Janus homology 2

JNK:

c-JUN N-terminal kinase/mitogen-activated protein kinase 8

kb:

Kilobase pairs

L:

C. elegans larval stage

LGE:

Lateral ganglionic eminence

LGR:

Leucine-rich repeat-containing G protein-coupled receptor

LIN-17:

Abnormal cell lineage-17

LIN-18:

Abnormal cell lineage-18

lio :

linotte

LRP:

Low-density lipoprotein receptor-related protein

MAP2:

Microtubule-associated protein 2

MB:

Drosophila mushroom body

MGE:

Medial ganglionic eminence

MIB1:

Mindbomb E3 ubiquitin protein ligase 1

MIG-1:

Abnormal cell migration-1

ML:

Medial–lateral axis

MOM-2:

more mesoderm-2

MOM-5:

more mesoderm-5

mRNA:

Messenger RNA

MuSK:

Muscle, skeletal, receptor tyrosine kinase

NCBI:

National Center for Biotechnology Information

NFATc:

Nuclear factor of activated T cells

NG2:

Neuron–glial antigen 2

NMJ:

Neuromuscular junction

NPC:

Neural progenitor cell

Nrt:

Neurotactin

OR:

Odorant receptor

ORN:

Olfactory receptor neuron

OT:

Optic tectum

P:

Postnatal

PC:

Posterior commissure

PCP:

Planar cell polarity

PCR:

Polymerase chain reaction

PDZ:

Postsynaptic density protein 95/discs large-1/zonula occludens-1

PK:

Protein kinase

PLR-1:

Cell polarity defective-1

PN:

Projection neuron

Psen:

Presenilin

PTK:

Protein tyrosine kinase

PTK7:

Protein tyrosine kinase 7

RRS:

Recessive Robinow syndrome

Rab5:

RAB5A member of the RAS oncogene family

Rβ:

Ryk β-amyloid-like fragment

RGC:

Retinal ganglion cell

RING:

Really interesting new gene

RNF43:

Ring finger protein 43

ROCK:

Rho-associated coiled-coil containing protein kinase 1 or 2

ROR:

Receptor tyrosine kinase-like orphan receptor

RT:

Reverse transcription

R spine:

Regulatory spine

RTK:

Receptor-type protein tyrosine kinase

RWD1:

Fully human anti-RYK (WIF domain-specific) monoclonal antibody

Ryk:

Related to tyrosine kinase

Ryk-CTF45:

Ryk carboxyl-terminal fragment of 45 kDa

Ryk-CTF55:

Ryk carboxyl-terminal fragment of 55 kDa

Ryk-FL:

Full-length Ryk lacking N-terminal signal peptide

Ryk-ICF:

Ryk intracellular fragment

Ryk-NTF:

Ryk amino-terminal fragment

S:

Svedberg unit

SC:

Superior colliculus

Scr :

sex combs reduced

Sema:

Semaphorin

sFRP2:

Secreted Fzd-related protein 2

SFK:

Src family kinase

SH2:

Src homology domain 2

SH3:

Src homology domain 3

siRNA:

Short interfering RNA

SOD1:

Superoxide dismutase 1, soluble

Src:

Src proto-oncogene, non-receptor tyrosine kinase

STYK1:

Serine/threonine/tyrosine kinase 1

TBC:

Tetrabasic cleavage

TCF/LEF:

T cell factor/lymphocyte enhancer factor

TGF-β:

Transforming growth factor-β

TM:

Transmembrane

TN:

Temporal–nasal axis

TRPC:

Transient receptor potential channel

TUJ1:

βIII-tubulin

UBC:

Ubiquitin C

Vangl2:

Van Gogh-like planar cell polarity protein 2

VM:

Ventral midbrain or ventral–medial axis

VNC:

Drosophila ventral nerve cord

VPC:

Vulval precursor cell

VZ:

Ventricular zone

WASF1:

WAS protein family, member 1

WG:

Wingless

WIF:

Wnt inhibitor factor

WNK:

With-no-lysine protein kinase

Wnt:

Wingless-related integration site

XRyk:

Xenopus Ryk

ZNRF3:

Zinc and ring finger 3

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Author information

Authors and Affiliations

  1. Tumour Angiogenesis Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002, VIC, Australia

    Michael M. Halford, Maria L. Macheda & Steven A. Stacker

  2. Locked Bag 1, A’Beckett Street, Melbourne, 8006, VIC, Australia

    Michael M. Halford

  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, 3010, VIC, Australia

    Steven A. Stacker

Authors
  1. Michael M. Halford
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  2. Maria L. Macheda
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  3. Steven A. Stacker
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Corresponding author

Correspondence to Michael M. Halford .

Editor information

Editors and Affiliations

  1. School of Medicine and Public Health Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Deric L. Wheeler

  2. Department of Biological Regulation, Rehovot, Israel

    Yosef Yarden

RYK receptor at a glance

RYK receptor at a glance

 

Humana

Mouseb

Gene location

3q22

9D1

Gene size (bp)

93,609

≈73 kb

Intron/exon numbers

14/15

14/15

mRNA size (5′, ORF, 3′)

2,942 bp

3,267 bp

Amino acid residues

610 (isoform 1 precursor), 607 (isoform 2 precursor), 273 (isoform 3 precursor)

594 (isoform 1 precursor), 591 (isoform 2 precursor), 475 (isoform 3 precursor)

Mature protein (predicted; kDa)

68 (isoform 1 precursor)

66 (isoform 1 precursor)

Posttranslational modifications

N-linked glycosylation, 5 (N139, N174, N178, N182, N209, N291)

Phosphorylation

Polyubiquitylation

Proteolytic cleavages

N-linked glycosylation, 5 (N123, N158, N162, N166, N193)

Phosphorylation

Polyubiquitylation

Proteolytic cleavages

Domains

WIF (66–194)

Transmembrane helix (228–255)

Protein tyrosine kinase (333–606)

WIF (50–178)

Transmembrane helix (212–239)

Protein tyrosine kinase (317–590)

Extracellular ligands

Wnts

Wnts

Known dimerizing partners

Self

EphB2

EphB3

Fzd8

Pathways activated

Wnt/β-catenin

Wnt/calcium dependent

Wnt/planar cell polarity

AKT

Wnt/β-catenin

Wnt/calcium dependent

Wnt/planar cell polarity

Tissues expressed (mRNA)

Adipose, adrenal gland, blood cells, brain, breast, cerebellum, colon

Colorectal adenocarcinoma

Endothelial cells, fallopian tube, heart, kidney, liver, lung, lymph node, ovary

Ovarian carcinoma, pancreas

Placenta, prefrontal cortex

Prostate, retina, salivary gland, skeletal muscle

Skin, small intestine, smooth muscle, spleen, spinal cord

Testis, thymus, thyroid

Tongue, tonsil, thyroid, uterus

Adipose, adrenal gland, bladder, bone, bone marrow

Brain, cerebellum, colon

Embryo, whole

Embryo, heart, brain, spinal cord, small intestine, eye, hair follicle

Hematopoietic stem cells

Hippocampus, kidney, liver

Lung, lymph node, mammary gland, ovary, pancreas

Placenta, prostate, retina

Salivary gland, skeletal muscle

Skin, small intestine, spleen

Stomach, striatum, testis, tongue, thymus, uterus

Human diseases

Cleft lip/palate, cancer (melanoma)

Cancer (medulloblastoma, non-melanoma skin)

Knockout mouse phenotype

–

Neonatal death on day of birth

Cleft of the secondary palate

Growth retardation

Craniofacial defects

Reduced long bone length

Defective callosal axon guidance

Reduced neuron differentiation and increased oligodendrocyte differentiation in forebrain

Open neural tube (craniorachischisis; interaction with Vangl2)

Open ventral body wall (interaction with Vangl2)

Defective forelimb digit formation (interaction with Vangl2)

Sternum and rib defects (interaction with Vangl2)

Defective polarity of hair cells in cochlea (interaction with Vangl2)

Additional row of hair cells in middle cochlea (interaction with Vangl2)

Eyelid closure defects (interaction with Vangl2)

  1. aHuman RYK protein numbering is based on the isoform 1 precursor (NCBI reference sequence NP_001005861.1)
  2. bMouse Ryk protein numbering is based on the isoform 1 precursor (NCBI reference sequence NP_038677.3)

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Halford, M.M., Macheda, M.L., Stacker, S.A. (2015). The RYK Receptor Family. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Family and Subfamilies. Springer, Cham. https://doi.org/10.1007/978-3-319-11888-8_15

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