In the previous chapter, the critical role of kinases performed by kinases in cellular activity was examined.  Cells regulate many intercellular proteins and pathways by controlling the addition of phosphate groups to specific amino acids by kinases.  Of course, such a system of regulation also requires enzymes which can remove phosphate groups so that an activated protein does not remain active indefinitely.  (For example, after a wound, certain cells might increase their rate of cell division in signal transduction pathways involving kinases.  Once the wound is healed, however, elevated rates of growth would no longer be appropriate.)  Phosphatases are enzymes which remove phosphate groups and often oppose the action of kinases.

     Protein tyrosine phosphatases (PTPs) possess a single phosphatase domain, similar to yeast PTPs, while receptor protein tyrosine phosphatases (RPTPs) possess two PTPase domains (Muller, 2001).  The protein tyrosine phosphatase group of genes (PTPase family) includes enzymes which are not functionally or structurally related other than homology at a conserved catalytic domain of about 240 amino acids.    One group of this family consists of cytoplasmic enzymes which are very low in molecular weight (low Mr PTPases) and are known from prokaryotes through vertebrates.  They have no similarity to other PTPases outside of the catalytic site.  The other groups of PTPases have not yet been identified in prokaryotes (Ramponi, 1997).  One group of PTPs remove phosphates from tyrosine residues while the dual specificity phosphatases (DSPs) can remove phosphates from serine and threonine residues.  Each is a separate family (van Huijsduijnen, 1998). 

     The addition and removal of phosphates from a variety of cellular molecules is essential for organisms.  The low molecular tyrosine phoshatases in mammals are homologous to arsenate reductase which protect bacteria and yeast from the toxic compound arsenate (Bennet, 2001). Growth factors typically possess protein tyrosine kinase domains and mutations which cause constitutive activity of kinases are a cause of cancer.  PTPases are not only functional in development and differentiation, they oppose the growth-causing effects of kinases, and can thus function as tumor suppressor genes (Ramponi, 1997).

      One DSP can remove phosphate from phosphatidylinositol (van Huijsduijnen, 1998).  Inositol 1,4,5-triphosphate and other inositol polyphosphates are important second messengers in cells.  The enzyme multiple inositol polyphosphate phosphatase (MIPP) removes the phosphates from these inositol polyphosphates which possess more than 4 phosphate groups.  These enzymes are known from both plants and animals (invertebrates and vertebrates) and form a distinct subfamily of histidine phosphatase enzymes (Chi, 1999).

     Plant and animal groups of protein phosphatases form separate groups, their branches having evolved after the split of animal and plant lineages.


Protein phosphatases include proteins encoded by two families of genes: PPP and PPM.  PPP genes are known in all groups of eukaryotes, although duplications have amplified the numbers of genes in higher eukaryotes (Lin, 1999).  The phosphatases of the haloacid dehalogenase superfamily have been conserved in eukaryotic cells to the point that yeast and mammalian enzymes can be substituted for one another. One member of this family functions in the formation of the neural tube (Kim, 2007).

     The phosphatases of mammalian genomes are similar.  There is only one protein-tyrosine-phosphatase which is known in rodents which does not exist as functional gene in humans.  The rodent OST-PTP gene is homologous to a pseudogene in humans (Cousin, 2004). 

     The many protein phosphatases of the human genome have resulted from the duplication and subsequent modification of a smaller number of ancestral enzymes.



Cancer can result from an improper balance between kinases and phosphatases.


PROTEIN-TYROSINE PHOSPHATASES, RECEPTOR-TYPE may possess 1 phosphatase domain or two domains in tandem separated by 56-57 amino acids. 


PTPRA is ubiquitously expressed.




PTPRC is a major molecule on the surface of leukocytes where it may comprise 10% of the cell surface.  It regulates proliferation, antiviral responses, and erythropoeitin response.  Mutations cause SCID and multiple sclerosis. (A lymphocyte is pictured be


PTPRD is expressed in hippocampal regions CA2 and CA3, on B lymphocytes, and the thymus.  Mutations in mice result in learning deficits.




PTPRF is a membrane protein which, in addition to two tyrosine phosphate domains, possesses a cytoplasmic domain which is homologous to PTPN1 and an extracellular domain homologous to NCAM (including 3 immunoglobulin domains and 8 fibronectin domains).  It is involved in cell-cell and cell-matrix interactions.


PTPRG is involved in tumor suppression for renal and lung tumors.  Its extracellular portion is similar to the enzyme carbonic anhydrase.


PTPRH possesses 8 fibronectin domains and is similar to PTPRB; it may be involved in some colorectal cancers.


PTPRI is only expressed by mesangial cells in the kidney. 


PTPRJ mutations can cause colon cancer.


PTPRK colocalizes with catenins at adhesions.


PTPRM s most highly expressed in the lung.


PTPRN only has one phosphatase domain (unlike most family members) and is expressed in the brain, pituitary, and pancreas.  It is an autoantigen in IDDM diabetes.


PTPRN2 is an autoantigen in IDDM diabetes.


PTPRO contains 8 fibronectin repeats.


PTPRR is produced as alternate transcripts.  One is transcribed throughout the brain, one almost exclusively in the cerebellum, and one throughout the body.  Cells of the cerebellum are depicted below.


PTPRS functions in the development of the nervous and neuroendocrine systems.


PTPRU localizes with catenin and cadherin and may be a signal of cell contact.


PTPRZ1 possesses an extracellular domain homologous to carbonic anhydrase.  It is only expressed in the CNS and is most highly expressed during development.


PTPRZ2 is highly homologous to PTPRZ2.  One transcript is only expressed in the brain.



PTPN1 inhibits insulin signaling and mutants are susceptible to insulin resistance.  Mutant mice are less likely to gain weight.


PTPN2 pseudogenes are known (two).




PTPN4 interacts with cytoskeletal proteins.


PTPN5 is more highly expressed in the striatum than in other brain regions.  It functions in neuron signaling and NMDA function.


PTPN6 is expressed early in hematopoeisis in all lineages.  It may oppose allergic asthma and mutations may cause leukemia.


PTPN7 is expressed primarily during hematopoeisis.


PTPN8 is functions in hematopoeisis and is expressed in the bone marrow, spleen, and thymus.


PTPN9 is expressed in many tissues.  One domain is similar to the retinaldehyde binding protein.


PTPN11 mutations cause Noonan Syndrome and leukemia.  It needed for gastrulation, hematopoeisis in the yolk sac, and for the development of semilunar valves.


PTPN12 regulates the proto-oncogene ABL and is involved in the inflammatory response.  Mutations can cause arthritis and colon cancer.


PTPN13 is the only phosphatase with a leucine zipper domain; it inhibits apoptosis.


PTPN14 possesses an ezrin-like domain.


PTPN18 can dephosphorylate the kinases which are often overexpressed in tumors.


PTPN21 is most highly expressed in the placenta, lung, and skeletal muscle.


PTPN22 has two isoforms in T cells whose expression levels change after activation.


PTPN23 possess a different amino acid sequence in the “invariant” phosphatase active center.  One mutations was involved with a lung cancer.  Lung cells are depicted below.



DUSP1 interacts with MAP kinases.


DUSP2 is involved in apoptotic pathways; p53 regulates it.




DUSP4 inhibits MAP kinase pathways.


DUSP5 inhibits MAP kinase pathways.


DUSP6 inactivates MAP kinase pathways and is most highly expressed in the heart and pancreas.


DUSP7 produces alternate transcripts.


DUSP8 is expressed in the developing CNS and ganglia; it is stimulated by NGF and insulin.


DUSP9 inactivates MAP kinase pathways.


DUSP11 seems to associates with RNA or ribonucleoproteins.


DUSP12 possesses a novel zinc finger domain and has its highest expression in the spleen, gonads, and leukocytes.  An ovarian follicle is pictured below.


DUSP16 binds ER2, p38 and JNK1.


C-TERMINAL DOMAIN OF RNA POLYMERASE II SUBUNIT A, PHOSPHATASE OF, SUBUNIT 1; CTDP1 is expressed in all tissues.  It interacts with general transcription factors and RNA Polymerase II subunit H.



PTP4A1 possesses 2 promoters and is one of the immediate-early genes.


PTP4A2 is overexpressed in some tumors.


PTP4A3 is more highly expressed in some colorectal cancers.








PPP1CA suppresses memory and learning.   PP1 is one of 4 major phosphatases which oppose protein kinases and has 3 catalytic subunits: A, B, and G. 










PPP4C is in the same chromosomal region where some leukemias map.


PPP5C is expressed in all tissues, localizes to the nucleus and is involved in the development of some tumors.


PPP6C functions in the regulation of the cell cycle.  Dividing nematode cells are pictured below.



PPM1A inhibits the stress response.


PPM1B is widely expressed with its highest expression in cardiac and skeletal muscle.


PPM1G has a large acidic domain and helps to form the spliceosome.


PPM1D can stop apoptosis when overexpressed and suppresses p53.  It is overexpressed in many cancers (such as 11% of breast cancers).


PPM2C is expressed in the heart, brain, and lung.




INPP1 misexpression can cause cardiac hypertrophy.


INPP4A is involved in PDGF and neutrophil activating pathways.


INPP4B is most highly expressed in striated muscle.






INPP5D is most highly expressed in the placenta and heart.