RIP4 is an ankyrin repeat-containing kinase essential for keratinocyte differentiation.
The epidermis is a stratified, continually renewing epithelium dependent on a balance among cell proliferation, differentiation, and death for homeostasis. In normal epidermis, a mitotically active basal layer gives rise to terminally differentiating keratinocytes that migrate outward and are ultimately sloughed from the skin surface as enucleated squames. Although many proteins are known to function in maintaining epidermal homeostasis, the molecular coordination of these events is poorly understood. RIP4 is a novel RIP (receptor-interacting protein) family kinase with ankyrin repeats cloned from a keratinocyte cDNA library. RIP4 deficiency in mice results in perinatal lethality associated with abnormal epidermal differentiation. The phenotype of RIP4(-/-) mice in part resembles that of mice lacking IKKalpha, a component of a complex that regulates NF-kappaB. Despite the similar keratinocyte defects in RIP4- and IKKalpha-deficient mice, these kinases function in distinct pathways. RIP4 functions cell autonomously within the keratinocyte lineage. Unlike IKKalpha, RIP4-deficient skin fails to fully differentiate when grafted onto a normal host. Instead, abnormal hair follicle development and epidermal dysplasia, indicative of progression into a more pathologic state, are observed. Thus, RIP4 is a critical component of a novel pathway that controls keratinocyte differentiation.
Holland
Pamela
P
Immunex Corporation, 51 University Street, Seattle, WA 98101, USA. hollandp@amgen.com
Willis
Cynthia
C
Kanaly
Suzanne
S
Glaccum
Moira
M
Warren
Annjanette
A
Charrier
Keith
K
Murison
J
J
Derry
Jonathan
J
Virca
G
G
Bird
Timothy
T
Peschon
Jacques
J
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D000078404:Epidermal Cells; D004817:Epidermis / Q000254:growth & development / Q000473:pathology / Q000502:physiology; D005260:Female; D006706:Homeostasis; D015603:Keratinocytes / Q000502:physiology*; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
D011506:Proteins; D007633:Keratins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C430884:Ripk4 protein, mouse